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Gene Review

KLK4  -  kallikrein-related peptidase 4

Homo sapiens

Synonyms: AI2A1, ARM1, EMSP, EMSP1, Enamel matrix serine proteinase 1, ...
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Disease relevance of KLK4

  • In addition, variant-specific RT-PCRs for the cloned KLK3 and KLK4 variants as well as for the "classical" forms of the six genes were used to determine their expression profiles in healthy tissues, their regulation by steroids, and their differential expression in prostate cancer [1].
  • Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells [2].
  • Significant correlations were identified among mRNA of KLK4, 5, 6, 7, 8, 9, 10, 11, 13, 14 and 15 in cancer cells isolated from ascites fluid [3].
  • Erythrocyte kallikrein-like esterase activity was greater in women without hypertension than in men without hypertension (p less than 0.05 to 0.001) when receiving the 9 and 109 mEq sodium diets, but values were similar in all groups receiving the 259 mEq sodium diet.(ABSTRACT TRUNCATED AT 250 WORDS)[4]
  • Kallikrein-like esteroprotease activity and kininase activity in submandibular gland from a mutant mouse with human cystic fibrosis like alterations [5].
  • Consistent with these data, small interfering RNA-mediated knockdown of endogenous KLK4 in LNCaP prostate cancer cells inhibits cell growth [6].
  • Immunohistochemical analysis indicated the co-expression of agonist and PAR-2 in primary prostate cancer and bone metastases, suggesting that KLK4 signaling via this receptor will have pathological relevance [7].

Psychiatry related information on KLK4


High impact information on KLK4


Chemical compound and disease context of KLK4


Biological context of KLK4

  • Localization of a new prostate-specific antigen-related serine protease gene, KLK4, is evidence for an expanded human kallikrein gene family cluster on chromosome 19q13.3-13.4 [19].
  • Given that introns <100 bp in length are retained in 95% of human genes and that splice variants of KLK3 and KLK4 retain intron III, we hypothesized that other proteins in this family, with a small intron III, may also retain it [1].
  • In this study, we sought to characterize the substrate specificity of KLK4 in order to gain insight into potential physiological roles of the enzyme [20].
  • Recombinant KLK4 was able to activate pro-PSA/KLK3 and degrade members of the insulin-like growth factor (IGF) binding protein (IGFBP) family [20].
  • KLK4 endometrial mRNA expression was greatest on days 0, 5, and 10 when compared with days 12, 15, and 17 of the estrous cycle and greater in cyclic compared with pregnant gilts [21].

Anatomical context of KLK4


Associations of KLK4 with chemical compounds


Physical interactions of KLK4


Enzymatic interactions of KLK4


Other interactions of KLK4

  • For KLK4, KLK8, and KLK13 mRNA, splice variants were identified to be their major mRNA species [29].
  • Unlike all other kallikreins, the KLK4-KLK15 encoded proteases are less related (25-44%) and do not contain a conventional kallikrein loop [30].
  • Using this methodology, three naturally processed CD4 epitopes derived from the KLK4 sequence are identified [22].
  • KLK4 concentrates at the enamel surface when the enamel matrix disappears, and aggressively degrades amelogenin in vitro [23].
  • The prostase cDNA encodes a putative 254-aa polypeptide with a conserved serine protease catalytic triad and an amino-terminal pre-propeptide sequence, indicating a potential secretory function [24].

Analytical, diagnostic and therapeutic context of KLK4


  1. Intron retention: a common splicing event within the human kallikrein gene family. Michael, I.P., Kurlender, L., Memari, N., Yousef, G.M., Du, D., Grass, L., Stephan, C., Jung, K., Diamandis, E.P. Clin. Chem. (2005) [Pubmed]
  2. Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells. Prezas, P., Arlt, M.J., Viktorov, P., Soosaipillai, A., Holzscheiter, L., Schmitt, M., Talieri, M., Diamandis, E.P., Krüger, A., Magdolen, V. Biol. Chem. (2006) [Pubmed]
  3. Kallikreins as markers of disseminated tumour cells in ovarian cancer - a pilot study. Oikonomopoulou, K., Scorilas, A., Michael, I.P., Grass, L., Soosaipillai, A., Rosen, B., Murphy, J., Diamandis, E.P. Tumour Biol. (2006) [Pubmed]
  4. Gender differences of human tissue kallikrein and an erythrocyte kallikrein-like enzyme in essential hypertension. Hughes, G.S., Margolius, H.S., Peters, R., Oexmann, M.J., Chao, J., Lindenmayer, G. J. Lab. Clin. Med. (1988) [Pubmed]
  5. Kallikrein-like esteroprotease activity and kininase activity in submandibular gland from a mutant mouse with human cystic fibrosis like alterations. Dodera Martínez, G., Vila, S.B., Catanzaro, O.L., Pivetta, O.H. Life Sci. (1988) [Pubmed]
  6. Kallikrein 4 is a proliferative factor that is overexpressed in prostate cancer. Klokk, T.I., Kilander, A., Xi, Z., Waehre, H., Risberg, B., Danielsen, H.E., Saatcioglu, F. Cancer Res. (2007) [Pubmed]
  7. Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. Ramsay, A.J., Dong, Y., Hunt, M.L., Linn, M., Samaratunga, H., Clements, J.A., Hooper, J.D. J. Biol. Chem. (2008) [Pubmed]
  8. Deficiency of kallikrein-like enzyme activities in cerebral tissue of patients with Alzheimer's disease. Aoyagi, T., Wada, T., Nagai, M., Kojima, F., Harada, S., Takeuchi, T., Takahashi, H., Hirokawa, K., Tsumita, T. Experientia (1990) [Pubmed]
  9. Human eosinophil-granule major basic protein and synthetic polycations induce airway hyperresponsiveness in vivo dependent on bradykinin generation. Coyle, A.J., Ackerman, S.J., Burch, R., Proud, D., Irvin, C.G. J. Clin. Invest. (1995) [Pubmed]
  10. Seminal vesicle-secreted proteins and their reactions during gelation and liquefaction of human semen. Lilja, H., Oldbring, J., Rannevik, G., Laurell, C.B. J. Clin. Invest. (1987) [Pubmed]
  11. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. Lilja, H. J. Clin. Invest. (1985) [Pubmed]
  12. Anaphylactic release of a basophil kallikrein-like activity. I. Purification and characterization. Newball, H.H., Berninger, R.W., Talamo, R.C., Lichtenstein, L.M. J. Clin. Invest. (1979) [Pubmed]
  13. Anaphylactic relase of a basophil kallikrein-like activity. II. A mediator of immediate hypersensitivity reactions. Newball, H.H., Talamo, R.C., Lichtenstein, L.M. J. Clin. Invest. (1979) [Pubmed]
  14. Compartmentalized expression of kallikrein 4 (KLK4/hK4) isoforms in prostate cancer: nuclear, cytoplasmic and secreted forms. Dong, Y., Bui, L.T., Odorico, D.M., Tan, O.L., Myers, S.A., Samaratunga, H., Gardiner, R.A., Clements, J.A. Endocr. Relat. Cancer (2005) [Pubmed]
  15. Distinctly different gene structure of KLK4/KLK-L1/prostase/ARM1 compared with other members of the kallikrein family: intracellular localization, alternative cDNA forms, and Regulation by multiple hormones. Korkmaz, K.S., Korkmaz, C.G., Pretlow, T.G., Saatcioglu, F. DNA Cell Biol. (2001) [Pubmed]
  16. Kallikrein 4 (KLK4), a new member of the human kallikrein gene family is up-regulated by estrogen and progesterone in the human endometrial cancer cell line, KLE. Myers, S.A., Clements, J.A. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  17. Purification and characterization of kallikrein from plasma of patients with acute pancreatitis. Toki, N., Sumi, H., Takasugi, S. Clin. Sci. (1981) [Pubmed]
  18. Changes in serotonin metabolism during migraine attacks. Kangasniemi, P.J. Monographs in neural sciences. (1976) [Pubmed]
  19. Localization of a new prostate-specific antigen-related serine protease gene, KLK4, is evidence for an expanded human kallikrein gene family cluster on chromosome 19q13.3-13.4. Stephenson, S.A., Verity, K., Ashworth, L.K., Clements, J.A. J. Biol. Chem. (1999) [Pubmed]
  20. Substrates of the prostate-specific serine protease prostase/KLK4 defined by positional-scanning peptide libraries. Matsumura, M., Bhatt, A.S., Andress, D., Clegg, N., Takayama, T.K., Craik, C.S., Nelson, P.S. Prostate (2005) [Pubmed]
  21. Porcine endometrial and conceptus tissue kallikrein 1, 4, 11, and 14 gene expression. Fernando, S.C., Buck, J.S., Ashworth, M.D., Ross, J.W., Geisert, R.D., Desilva, U. Reproduction (2006) [Pubmed]
  22. Identification of naturally processed CD4 T cell epitopes from the prostate-specific antigen kallikrein 4 using peptide-based in vitro stimulation. Hural, J.A., Friedman, R.S., McNabb, A., Steen, S.S., Henderson, R.A., Kalos, M. J. Immunol. (2002) [Pubmed]
  23. Expression, structure, and function of enamel proteinases. Simmer, J.P., Hu, J.C. Connect. Tissue Res. (2002) [Pubmed]
  24. 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]
  25. Higher human kallikrein gene 4 (KLK4) expression indicates poor prognosis of ovarian cancer patients. Obiezu, C.V., Scorilas, A., Katsaros, D., Massobrio, M., Yousef, G.M., Fracchioli, S., Rigault de la Longrais, I.A., Arisio, R., Diamandis, E.P. Clin. Cancer Res. (2001) [Pubmed]
  26. Tissue kallikrein and bradykinin do not have direct insulin-like actions on skeletal muscle glucose utilization. Shimojo, N., Pickens, T.G., Margolius, H.S., Mayfield, R.K. Biol. Chem. Hoppe-Seyler (1987) [Pubmed]
  27. The contact system in human malignant and benign ascites. Buø, L., Karlsrud, T.S., Johansen, H.T., Aasen, A.O. Scand. J. Clin. Lab. Invest. (1993) [Pubmed]
  28. Kallikrein-like enzyme from the venom of Agkistrodon p. piscivorus. Nikai, T., Imai, K., Nagasaka, M., Sugihara, H. Int. J. Biochem. (1988) [Pubmed]
  29. Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages. Komatsu, N., Takata, M., Otsuki, N., Toyama, T., Ohka, R., Takehara, K., Saijoh, K. J. Invest. Dermatol. (2003) [Pubmed]
  30. The expanded human kallikrein (KLK) gene family: genomic organisation, tissue-specific expression and potential functions. Clements, J., Hooper, J., Dong, Y., Harvey, T. Biol. Chem. (2001) [Pubmed]
  31. 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]
  32. Characterization of KLK4 expression and detection of KLK4-specific antibody in prostate cancer patient sera. Day, C.H., Fanger, G.R., Retter, M.W., Hylander, B.L., Penetrante, R.B., Houghton, R.L., Zhang, X., McNeill, P.D., Filho, A.M., Nolasco, M., Badaro, R., Cheever, M.A., Reed, S.G., Dillon, D.C., Watanabe, Y. Oncogene (2002) [Pubmed]
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