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Gene Review

KLK3  -  kallikrein-related peptidase 3

Homo sapiens

Synonyms: APS, Gamma-seminoprotein, KLK2A1, Kallikrein-3, P-30 antigen, ...
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Disease relevance of KLK3

  • For example, prostate-specific antigen (or KLK3) is a secreted protein that is widely used as a diagnostic marker for prostate cancer [1].
  • Short sequence repeat polymorphisms for the human plasma kallikrein gene (KLKB1; previously known as KLK3) on chromosome 4 were associated with ESRD in an African American study population [2].
  • RT-PCR for PSA, hK2-L, and hK2-U were positive in 24, 25, and 26%, respectively, of prostatectomy patients; 88, 71, and 86%, respectively, of patients with metastases to bones; 7, 14, and 36%, respectively, of healthy men [3].
  • Recombinant pro-PSA was expressed in Escherichia coli, isolated from inclusion bodies, refolded, and purified [4].
  • Prostate-specific antigen (PSA) is a well-established tumor marker of prostatic adenocarcinoma [5].
  • Taken together with the finding that the G-158A polymorphism is associated with an increased risk of prostate cancer in Australian men, our functional data suggest that the presence of the A allele in AREI may, in part, account for the altered PSA regulation seen in prostate cancer [6].
  • In a prospective cohort of men enrolled into expectant management for prostate cancer, serum and tissue levels of proPSA at diagnosis are associated with need for subsequent treatment [7].

Psychiatry related information on KLK3

  • However, the effect of physical activity on the PSA concentration in serum is controversial [8].
  • PRACTICE IMPLICATIONS: This brief pDA could serve as an acceptable and low cost adjunct to counselling by the General Practitioner (GP), and should promote informed decision making regarding the PSA test [9].
  • A sensitive sandwich enzyme immunoassay for gamma-seminoprotein and its application to sex discrimination of blood and bloodstains [10].
  • There was no increase in the HADS scores, or reduction in the SF-12 mental health component summary score, on attendance at the biopsy clinic after receiving an 'abnormal' PSA result [11].
  • As the risk for such progression is higher in patients with larger glands or higher serum PSA values at baseline, it is in those patients that finasteride induces an even greater risk reduction, making it a cost-effective treatment choice for patients with LUTS associated with prostatic enlargement [12].

High impact information on KLK3

  • Reporting in this issue of Cell, Kasper and colleagues (Mazmanian et al., 2005) reveal that a bacterial polysaccharide, PSA, produced by the commensal bacterium Bacteroides fragilis directs development of the immune system of the mouse host [13].
  • We conclude that PSA is more sensitive than PAP in the detection of prostatic cancer and will probably be more useful in monitoring responses and recurrence after therapy [14].
  • PSA was increased in 86 percent and PAP in 14 percent of the patients with benign prostatic hyperplasia [14].
  • This test detects as little as 3 ng of the p30 antigen per milliliter in various body fluids [15].
  • The p30 antigen was detectable in vaginal fluid for a mean period of 27 hours after coitus, as compared with 14 hours for prostatic acid phosphatase [15].

Chemical compound and disease context of KLK3


Biological context of KLK3

  • KLK15 is newly discovered kallikrein gene that is located adjacent to KLK3 on chromosome 19q13 [19].
  • The human kallikrein gene cluster, located in the chromosome band 19q13, contains several tissue-specific serine protease genes including the prostate-specific KLK2, KLK3 and prostase genes [20].
  • Fifteen kallikrein genes were located in the chimpanzee (Pan troglodytes) genome, while only 14 were identified in the canine (Canis familiaris) genome as no orthologue to human KLK3 was found [21].
  • Our study suggests that in addition to the four AREs identified in the PSA enhancer core, another regulatory element (GAGATA), which is located at the region designated PSA3.1, also contributes to transcriptional regulation by androgens [22].
  • The main activity of this 5.8-kb PSA promoter resides in a 455-bp enhancer core region located about 4 kb upstream of the TATA box [22].

Anatomical context of KLK3


Associations of KLK3 with chemical compounds

  • Together, our data indicate that VES may suppress androgen/AR-mediated cell growth and PSA expression by inhibiting AR expression at both the transcription and translation levels [16].
  • Moreover, DIM inhibited endogenous PSA transcription and reduced intracellular and secreted PSA protein levels induced by DHT in LNCaP cells [27].
  • A binding motif is present in the PSA and hGK-1 promoters, closely resembling the consensus sequence for steroid-responsive elements [28].
  • Treatment of cells with cycloheximide demonstrates that, while PSA/hGK-1 basal transcription strictly depends on continuous protein synthesis, transcriptional induction by androgen does not [28].
  • A weak correlation was observed between urinary PSA and serum 3 alpha-androstanediol glucuronide (r(s) = 0.42, P = 0.03) as well as between urinary PSA and serum testosterone (r(s) = 0.40, P = 0.04) [5].

Physical interactions of KLK3


Enzymatic interactions of KLK3

  • Autoradiographs measuring IGFBP-3 protease activity demonstrated that purified PSA cleaved IGFBP-3, yielding a cleavage pattern identical to that of seminal plasma [34].
  • PCI was found to inhibit the PSA-catalyzed degradation of insoluble coagula Sg I + II by forming a PSA-PCI complex [35].
  • Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments [36].
  • CONCLUSIONS: Most PSA in BPH nodules is in the nicked form with low chymotrypsin-like activity [37].
  • The up-regulated PSA expression is a function of the level of the phosphorylated AR (r = 0.9814), but not the dephosphorylated form of the receptor protein (r = 0.4808) [38].

Co-localisations of KLK3

  • The hGK-1 mRNA was colocalized with PSA mRNA in prostatic epithelia [39].

Regulatory relationships of KLK3

  • Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM [17].
  • The production of PSA protein appears to be under the control of circulating androgens acting through the androgen receptor [40].
  • EGFR signaling pathway negatively regulates PSA expression and secretion via the PI3K-Akt pathway in LNCaP prostate cancer cells [41].
  • The chymotryptic activity of PSA was further confirmed by the ability of alpha-1-antichymotrypsin and chymostatin to block PSA cleavage of radiolabeled IGFBP-3.(ABSTRACT TRUNCATED AT 250 WORDS)[42]
  • Recombinant prostin readily activates the precursor of PSA (pro-PSA) by cleavage of the amino terminal Arg(7)-Ile(8) peptide bond [43].

Other interactions of KLK3

  • Whether hK2 can be expressed, like PSA, in nonprostatic cells is not known [26].
  • The third human tissue kallikrein to be identified, hK2, could be an alternate or complementary marker to kallikrein hK3 (prostate-specific antigen) for prostate diseases [44].
  • These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells [45].
  • We speculate that PSA may serve to modulate IGF function within the reproductive system or in prostate cancer by altering IGF-IGFBP-3 interactions [34].
  • IGFBP-2 and -4 in seminal plasma were not degraded by PSA [34].

Analytical, diagnostic and therapeutic context of KLK3


  1. Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer. Xi, Z., Klokk, T.I., Korkmaz, K., Kurys, P., Elbi, C., Risberg, B., Danielsen, H., Loda, M., Saatcioglu, F. Cancer Res. (2004) [Pubmed]
  2. Genomic structure of the human plasma prekallikrein gene, identification of allelic variants, and analysis in end-stage renal disease. Yu, H., Anderson, P.J., Freedman, B.I., Rich, S.S., Bowden, D.W. Genomics (2000) [Pubmed]
  3. Preoperative blood reverse transcriptase-PCR assays for prostate-specific antigen and human glandular kallikrein for prediction of prostate cancer progression after radical prostatectomy. Shariat, S.F., Gottenger, E., Nguyen, C., Song, W., Kattan, M.W., Andenoro, J., Wheeler, T.M., Spencer, D.M., Slawin, K.M. Cancer Res. (2002) [Pubmed]
  4. Characterization of the precursor of prostate-specific antigen. Activation by trypsin and by human glandular kallikrein. Takayama, T.K., Fujikawa, K., Davie, E.W. J. Biol. Chem. (1997) [Pubmed]
  5. Prostate-specific antigen and human glandular kallikrein 2 are markedly elevated in urine of patients with polycystic ovary syndrome. Obiezu, C.V., Scorilas, A., Magklara, A., Thornton, M.H., Wang, C.Y., Stanczyk, F.Z., Diamandis, E.P. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  6. PSA/KLK3 AREI promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility. Lai, J., Kedda, M.A., Hinze, K., Smith, R.L., Yaxley, J., Spurdle, A.B., Morris, C.P., Harris, J., Clements, J.A. Carcinogenesis (2007) [Pubmed]
  7. Pro-prostate-specific antigen measurements in serum and tissue are associated with treatment necessity among men enrolled in expectant management for prostate cancer. Makarov, D.V., Isharwal, S., Sokoll, L.J., Landis, P., Marlow, C., Epstein, J.I., Partin, A.W., Carter, H.B., Veltri, R.W. Clin. Cancer Res. (2009) [Pubmed]
  8. Physical activity releases prostate-specific antigen (PSA) from the prostate gland into blood and increases serum PSA concentrations. Oremek, G.M., Seiffert, U.B. Clin. Chem. (1996) [Pubmed]
  9. Informed decision making and prostate specific antigen (PSA) testing for prostate cancer: A randomised controlled trial exploring the impact of a brief patient decision aid on men's knowledge, attitudes and intention to be tested. Watson, E., Hewitson, P., Brett, J., Bukach, C., Evans, R., Edwards, A., Elwyn, G., Cargill, A., Austoker, J. Patient education and counseling. (2006) [Pubmed]
  10. A sensitive sandwich enzyme immunoassay for gamma-seminoprotein and its application to sex discrimination of blood and bloodstains. Yukawa, N., Kohno, T., Ishikawa, E., Takahama, K. Forensic Sci. Int. (1992) [Pubmed]
  11. Measuring the psychosocial impact of population-based prostate-specific antigen testing for prostate cancer in the UK. Brindle, L.A., Oliver, S.E., Dedman, D., Donovan, J.L., Neal, D.E., Hamdy, F.C., Lane, J.A., Peters, T.J. BJU Int. (2006) [Pubmed]
  12. 5-alpha-Reductase Inhibitors Prevent the Progression of Benign Prostatic Hyperplasia. Roehrborn, C.G. Reviews in urology. (2003) [Pubmed]
  13. Sugar-coated regulation of T cells. Eynon, E.E., Zenewicz, L.A., Flavell, R.A. Cell (2005) [Pubmed]
  14. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. Stamey, T.A., Yang, N., Hay, A.R., McNeal, J.E., Freiha, F.S., Redwine, E. N. Engl. J. Med. (1987) [Pubmed]
  15. Postcoital detection of a male-specific semen protein. Application to the investigation of rape. Graves, H.C., Sensabaugh, G.F., Blake, E.T. N. Engl. J. Med. (1985) [Pubmed]
  16. Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells. Zhang, Y., Ni, J., Messing, E.M., Chang, E., Yang, C.R., Yeh, S. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  17. Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells. Blaszczyk, N., Masri, B.A., Mawji, N.R., Ueda, T., McAlinden, G., Duncan, C.P., Bruchovsky, N., Schweikert, H.U., Schnabel, D., Jones, E.C., Sadar, M.D. Clin. Cancer Res. (2004) [Pubmed]
  18. Effect of Calcitriol on Prostate-Specific Antigen In vitro and in Humans. Beer, T.M., Garzotto, M., Park, B., Mori, M., Myrthue, A., Janeba, N., Sauer, D., Eilers, K. Clin. Cancer Res. (2006) [Pubmed]
  19. The androgen-regulated gene human kallikrein 15 (KLK15) is an independent and favourable prognostic marker for breast cancer. Yousef, G.M., Scorilas, A., Magklara, A., Memari, N., Ponzone, R., Sismondi, P., Biglia, N., Abd Ellatif, M., Diamandis, E.P. Br. J. Cancer (2002) [Pubmed]
  20. Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19q13 region. Gan, L., Lee, I., Smith, R., Argonza-Barrett, R., Lei, H., McCuaig, J., Moss, P., Paeper, B., Wang, K. Gene (2000) [Pubmed]
  21. In silico identification and Bayesian phylogenetic analysis of multiple new mammalian kallikrein gene families. Elliott, M.B., Irwin, D.M., Diamandis, E.P. Genomics (2006) [Pubmed]
  22. Identification of a novel transcription factor, GAGATA-binding protein, involved in androgen-mediated expression of prostate-specific antigen. Wang, C., Yeung, F., Liu, P.C., Attar, R.M., Geng, J., Chung, L.W., Gottardis, M., Kao, C. J. Biol. Chem. (2003) [Pubmed]
  23. Glandular kallikreins and prostate-specific antigen are expressed in the human endometrium. Clements, J., Mukhtar, A. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  24. Identification and characterization of KLK14, a novel kallikrein serine protease gene located on human chromosome 19q13.4 and expressed in prostate and skeletal muscle. Hooper, J.D., Bui, L.T., Rae, F.K., Harvey, T.J., Myers, S.A., Ashworth, L.K., Clements, J.A. Genomics (2001) [Pubmed]
  25. Molecular cloning and characterization of prostase, an androgen-regulated serine protease with prostate-restricted expression. Nelson, P.S., Gan, L., Ferguson, C., Moss, P., Gelinas, R., Hood, L., Wang, K. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  26. Expression of human prostate-specific glandular kallikrein protein (hK2) in the breast cancer cell line T47-D. Hsieh, M.L., Charlesworth, M.C., Goodmanson, M., Zhang, S., Seay, T., Klee, G.G., Tindall, D.J., Young, C.Y. Cancer Res. (1997) [Pubmed]
  27. Plant-derived 3,3'-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells. Le, H.T., Schaldach, C.M., Firestone, G.L., Bjeldanes, L.F. J. Biol. Chem. (2003) [Pubmed]
  28. Transcriptional regulation of prostate kallikrein-like genes by androgen. Wolf, D.A., Schulz, P., Fittler, F. Mol. Endocrinol. (1992) [Pubmed]
  29. Complex formation between PSA isoenzymes and protease inhibitors. Leinonen, J., Zhang, W.M., Stenman, U.H. J. Urol. (1996) [Pubmed]
  30. Genotyping of AR and PSA polymorphisms in a patient with Klinefelter syndrome, non-Hodgkin lymphoma, and adenocarcinoma of the prostate. Mattos Dos Santos, R., Aparecida Rainho, C., Carlos Souza Trindade, J., Carlos Souza Trindade Filho, J., Lauro Viana De Camargo, J., Regina Rogatto, S. Cancer Genet. Cytogenet. (2004) [Pubmed]
  31. Structure, function, and regulation of the enzyme activity of prostate-specific antigen. Lilja, H. World journal of urology. (1993) [Pubmed]
  32. Biochemistry of prostate specific antigen, PSA. Malm, J., Lilja, H. Scand. J. Clin. Lab. Invest. Suppl. (1995) [Pubmed]
  33. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. Cohen, P., Peehl, D.M., Graves, H.C., Rosenfeld, R.G. J. Endocrinol. (1994) [Pubmed]
  34. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. Cohen, P., Graves, H.C., Peehl, D.M., Kamarei, M., Giudice, L.C., Rosenfeld, R.G. J. Clin. Endocrinol. Metab. (1992) [Pubmed]
  35. Characterization of semenogelin II and its molecular interaction with prostate-specific antigen and protein C inhibitor. Kise, H., Nishioka, J., Kawamura, J., Suzuki, K. Eur. J. Biochem. (1996) [Pubmed]
  36. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Iwamura, M., Hellman, J., Cockett, A.T., Lilja, H., Gershagen, S. Urology (1996) [Pubmed]
  37. Prostate specific antigen in benign prostatic hyperplasia: purification and characterization. Chen, Z., Chen, H., Stamey, T.A. J. Urol. (1997) [Pubmed]
  38. Synergistic effect of estramustine and [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) on the inhibition of androgen receptor phosphorylation in LNCaP cells. Wang, L.G., Liu, X.M., Budman, D.R., Kreis, W. Biochem. Pharmacol. (1999) [Pubmed]
  39. Tissue-specific and hormonal regulation of human prostate-specific glandular kallikrein. Young, C.Y., Andrews, P.E., Montgomery, B.T., Tindall, D.J. Biochemistry (1992) [Pubmed]
  40. Prostate-specific antigen and prostatic acid phosphatase: biomolecular and physiologic characteristics. Bilhartz, D.L., Tindall, D.J., Oesterling, J.E. Urology (1991) [Pubmed]
  41. EGFR signaling pathway negatively regulates PSA expression and secretion via the PI3K-Akt pathway in LNCaP prostate cancer cells. Hakariya, T., Shida, Y., Sakai, H., Kanetake, H., Igawa, T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  42. Biochemical analysis of prostate specific antigen-proteolyzed insulin-like growth factor binding protein-3. Fielder, P.J., Rosenfeld, R.G., Graves, H.C., Grandbois, K., Maack, C.A., Sawamura, S., Ogawa, Y., Sommer, A., Cohen, P. Growth Regul. (1994) [Pubmed]
  43. Activation of prostate-specific antigen precursor (pro-PSA) by prostin, a novel human prostatic serine protease identified by degenerate PCR. Takayama, T.K., Carter, C.A., Deng, T. Biochemistry (2001) [Pubmed]
  44. Serpin-derived peptide substrates for investigating the substrate specificity of human tissue kallikreins hK1 and hK2. Bourgeois, L., Brillard-Bourdet, M., Deperthes, D., Juliano, M.A., Juliano, L., Tremblay, R.R., Dubé, J.Y., Gauthier, F. J. Biol. Chem. (1997) [Pubmed]
  45. Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway. Lee, S.O., Lou, W., Hou, M., Onate, S.A., Gao, A.C. Oncogene (2003) [Pubmed]
  46. A prostate-specific antigen-like protein associated with renal cell carcinoma in women. Clements, J., Ward, G., Kaushal, A., Hi, S.I., Kennett, C., Nicol, D. Clin. Cancer Res. (1997) [Pubmed]
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