The Tissue Kallikrein Family of Serine Proteases: Functional Roles in Human Disease and Potential as Clinical Biomarkers

Abstract

Prostate specific antigen (PSA) or human kallikrein 3 (hK3) has long been an effective biomarker for prostate cancer. Now, other members of the tissue kallikrein (KLK) gene family are fast becoming of clinical interest due to their potential as prognostic biomarkers. particularly for hormone dependent cancers. The tissue kallikreins are serine proteases that are encoded by highly conserved multi-gene family clusters in rodents and humans. The rat and mouse loci contain 10 and 25 functional genes, respectively, while the human locus at 19q 13.4 contains 15 genes. The structural organization and size of these genes are similar across species; all genes have 5 coding exons that encode a prepro-enzyme. Although the physiological activators of these zymogens have not been described, in vitro biochemical studies show that some kallikreins can auto-activate and others can activate each other, suggesting that the kallikreins may participate in an enzymatic cascade similar to that of the coagulation cascade. These genes are expressed, to varying degrees, in a wide range of tissues suggesting a functional involvement in a diverse range of physiological and pathophysiological processes. These include roles in normal skin desquamation and psoriatic lesions, tooth development, neural plasticity, and Alzheimer's disease (AD). Of particular interest is the expression of many kallikreins in prostate, ovarian, and breast cancers where they are emerging as useful prognostic indicators of disease progression.

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

“…This gene family shows diverse patterns of evolution, with different species containing different numbers and combinations of loci [62]. Kallikrein 2 and PSA may be restricted to humans and dogs, which is interesting given the notably-high prevalence of prostate cancer in these two species [63].…”

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

“…At least seven kallikrein proteins are up-regulated in ovarian cancer compared with normal ovarian tissues (Yousef et al, 2003b). The prognostic value of at least 11 out of 15 members of the human kallikrein family in ovarian cancer has been also published (Clements et al, 2004;Yousef et al, 2005;Prezas et al, 2006;Dorn et al, 2007). Six kallikreins, KLK4, KLK5, KLK6, KLK7, KLK10, and KLK15 (Kim et al, 2001;Kyriakopoulou et al, 2003;Shvartsman et al, 2003;Yousef et al, 2003c;Kountourakis et al, 2008), are markers of poor prognosis in ovarian cancer.…”

Kallikrein Activates Prothrombin

“…demonstrates that 10 μg/mL kallikrein, that is about 25% of the normal plasmatic concentration of prekallikrein, generates about 15 mIU/mL K allikrein is a very important enzyme in coagulation, fibrinolysis, inflammation, and cell growth [1][2][3][4][5][6][7][8][9][10][11][12][13] ; kallikrein activates the contact phase enzymes of coagulation, kallikrein converts the important fibrinolysis proenzyme single-chain urokinse into the active enzyme urokinase, 14 kallikrein amplificates inflammation, and kallikrein affects cell growth. This study was undertaken to determine whether this interesting enzyme with so many substrates also directly activates prothrombin to thrombin, the most important enzyme of hemostasis.…”