Abstract
The tissue or glandular kallikreins (KLK) are members of a highly conserved multigene family encoding serine proteases that are central to many biological processes. The rodent KLK families are large, highly conserved and clustered at one locus. The human KLK gene family is clustered on chromosome 19q13.3-13.4, and until recently consisted of just three members. However, recent studies have identified up to 11 new members of the KLK family that are less conserved than their rodent counterparts. Using a Southern blot and sequence analysis of 10 BACs and cosmids spanning approximately 400 kilobases (kb) either side of the original KLK 60-kb locus, we demonstrated that these genes also lie adjacent to this. We have also clarified the position of several microsatellite markers in relation to the extended KLK locus. Moreover, from Southern blot analysis of the cosmids and BACs with a degenerate oligonucleotide probe to the histidine-encoding region of serine proteases, we have shown that there are no other serine protease genes approximately 400 kb centromeric and 220 kb telomeric of the extended locus. We performed an extensive analysis of the expression patterns of these genes by poly(A)(+) RNA dot blot and reverse transcriptase-polymerase chain reaction analysis, and demonstrated a diverse pattern of expression. Of interest are clusters of genes with high prostate (KLK2-4) and pancreatic (KLK6-13) expression suggesting evolutionary conservation of elements conferring tissue specificity. From these findings, it is likely that the human KLK gene family consists of just 14 clustered genes within 300 kb and thus is of a comparable size to the rodent families (13-24 genes within 310 and 480 kb, respectively). In contrast to the rodent families, the newest members of the human KLK family are much less conserved in sequence (23-44% at the protein level) and appear to consist of at least four subfamilies. In addition, like the rat, these genes are expressed at varying levels in a diverse range of tissues although they exhibit quite distinct patterns of expression.
Highlights
From the ‡Centre for Molecular Biotechnology, School of Life Sciences, Queensland University of Technology, Brisbane, Queensland 4001, Australia, and the ¶Lawrence Livermore National Laboratory, Livermore, California 94551
The glandular or tissue kallikreins are a subgroup of serine proteases highly conserved across several species, that are involved in the post-translational processing of polypeptides to their bioactive or inactive forms, a function that underlies and is central to most biological events [1]
Whereas KLK2 and KLK3 are primarily expressed at high levels in the secretory epithelium of the prostatic ducts and have been implicated in normal prostatic function as well as in cancer progression [8], tissue kallikrein, through its multifunctional roles, is involved in thephysiology of the kidney, brain, and respiratory, gastrointestinal, and reproductive tracts [2]
Summary
Vol 275, No 48, Issue of December 1, pp. 37397–37406, 2000 Printed in U.S.A. Tissue-specific Expression Patterns and Fine Mapping of the Human Kallikrein (KLK) Locus on Proximal 19q13.4*. The tissue or glandular kallikreins (KLK) are members of a highly conserved multigene family encoding serine proteases that are central to many biological processes. Whereas KLK2 and KLK3 are primarily expressed at high levels in the secretory epithelium of the prostatic ducts and have been implicated in normal prostatic function as well as in cancer progression [8], tissue kallikrein, through its multifunctional roles, is involved in the (patho)physiology of the kidney, brain, and respiratory, gastrointestinal, and reproductive tracts [2] This diverse functionality is underscored by the ubiquitous expression pattern observed for KLK1 in the rat [9]. Phylogenetic analysis of the 14 serine proteases encoded by the KLK genes of this locus demonstrated the extent of divergence within the expanded family and suggested that there are at least four human KLK subfamilies
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