Review article
Kallikrein and kinin receptor genes

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Abstract

Recent evidence increasingly supports the view that kinins exercise an important regulatory control in inflammation and in the growth and proliferation of cancer cells. The induction of tissue kallikrein (TK) gene results in either increased or new expression of this protease, resulting in an increased capacity to form kinins. The cellular actions of kinins are initiated and controlled by kinin B1 and B2 receptors. This review collates in detail current knowledge on the molecular profile and status of TK (hKLK1, hKLK2, and hKLK3) and the kinin B1 and B2 receptor genes. The development of TK inhibitors, as well as kinin receptor antagonists, for use in immune-modulated disorders and in tumours may provide a new generation of drugs of therapeutic value.

Introduction

The regulatory control exercised by kallikrein forms an intricate, endogenous cascade, thought to be involved in the regulation of cellular events that are believed to fulfill a role in post-translational processing of polypeptides Clements 1994, Yu et al. 1998. The cascade encompasses serine proteases (kallikrein enzymes); the multifunctional protein precursor kininogen; and the vasoactive peptides, kinins, which influence vascular function. Kallikreins are divided into two groups: plasma and tissue kallikrein (TK), and they differ in molecular weight, pI, substrate specificity, immunological characteristics, type of kinin released, and functional importance (Bhoola et al., 1992b). These proteases are encountered in biological fluids, tissues, and neutrophils (Bhoola et al., 1992b). Regulatory processes, such as organ perfusion, systemic blood pressure, sodium and water homeostasis, regulation and maturation of growth factors, and inflammation, are regulated by the humorally generated kinins Chen et al. 1988, Yu et al. 1998. The kinin peptides liberated from kininogens by the enzymic action of kallikreins are active biological peptides that participate in a wide range of physiological effects. Kinins exert their action via two known receptors; namely, kinin B1 and B2 receptors (Regoli & Barabe 1980, Vavrek & Stewart 1985; el-Dahr et al., 1997; Ma et al. 1994b, Pesquero & Bader 1998).

Plasma kallikrein (PK, EC 3.4.21.34) is a serine protease that occurs in mammalian plasma Mandle et al. 1976, Bouma et al. 1980, Motta et al. 1992. PK is involved in surface-dependent activation of blood clotting, fibrinolysis, kinin generation, and inflammation. A series of proenzymes, factor XII (H-kininogen, HK), plasma prekallikrein (PPK), factor XI, and high-molecular-weight kininogen (HK), contribute to the activation cascade Chung et al. 1986, Kaplan & Silverberg 1987. PPK, a glycoprotein precursor of PK, is synthesised and secreted by hepatocytes (Henderson et al., 1992), forms a complex with HK, and circulates in the plasma attached to the external surface membrane of the neutrophil (Henderson et al., 1994). When Hageman factor is activated, either by interaction with neutrophil or endothelial membranes or by binding to negatively charged molecules or tissue surfaces, it enzymatically converts PPK to PK. Through a feedback mechanism, further and rapid activation of Hageman factor occurs, with cyclical conversion of PPK to PK, resulting in the local formation of kinins from kininogen Bhoola et al. 1992b, Borges & Kouyoumdjian 1992, Chung et al. 1986, Hermann et al. 1999.

TK (EC 3.4.21.35), otherwise known as glandular kallikrein, was first discovered in urine as a hypotensive material (Frey & Kraut, 1928). TKs are acid glycoproteins, which unlike trypsin, have a high specificity for polypeptide substrate cleavage. Their principal function is thought to be the highly selective cleavage of the plasma protein kininogen at two peptide bonds to release kallidin (Lys-bradykinin) Drinkwater et al. 1988, Werle et al. 1937, Werle et al. 1961, MacDonald et al. 1988.

TK has been isolated and identified in various tissues Werle & Korsten 1938, Frey et al. 1950. Immunoreactive or kallikrein-like enzyme activity has been demonstrated in submandibular gland Ashley & MacDonald 1985a, Ashley & MacDonald 1985b, Mason et al. 1983, pancreas Ashley & MacDonald 1985b, Wolf et al. 1998, kidney Cumming et al. 1994, Figueroa et al. 1988, Naicker et al. 1999, spleen Chao et al. 1984, Wolf et al. 1998, pituitary gland (Jones et al., 1992a), placenta (Hermann et al., 1996), salivary gland Hofmann et al. 1983, Jenzano et al. 1992, Wolf et al. 1998, hypothalamus (Snyman et al., 1994), neutrophils Figueroa & Bhoola 1989, Naidoo et al. 1999, and brain Chao et al. 1983, Chao et al. 1987, Raidoo & Bhoola 1998, Raidoo et al. 1996. The regulatory mechanisms that govern the biosynthesis of TK in the various tissues are of particular interest, and the study of the molecular biology of the TK genes is of value in this regard.

Section snippets

Plasma kallikrein

The complementary DNA (cDNA) sequences of PK in the rat, mouse, and human have been established Chung et al. 1986, Seidah et al. 1989, Seidah et al. 1990. PK is coded for by a single gene that was determined in the rat by Southern blot analysis Seidah et al. 1989, Shine et al. 1983. In the rat, PK cDNA contains 2456 nucleotides, with a 2082 nucleotide long open reading frame. This PK gene is composed of 15 exons and 14 introns. Sequence analysis of human and rat PK shows an overall homology of

Profile of kinin receptor genes

Kinins are biologically active peptides thought to be involved in inflammation, pain generation, and regulation of blood pressure (Figueroa et al., 1990), and exert their actions via the kinin receptors Regoli & Barabe 1980, Schanstra et al. 1999. The binding of radiolabelled bradykinin to membrane preparations from rat and guinea pig brain and bovine cerebellum was first reported by Innis et al. (1981). Manning and Snyder (1983) later localised the receptors in guinea pig and canine spinal

Kallikrein genes in cancer

The kallikrein-kinin system (KKS) has been implicated in the process of tumourigenesis through the biological actions of kinins Robert & Gulick 1989, Maeda et al. 1999. TK is known to be present in several tumours, and may affect tumour growth and proliferation by a number of mechanisms. Preliminary reports indicate that TK is present in tumours of the breast (ductal breast cancer cells; Hermann et al. 1995, Rehbock et al. 1995), lung (Lewis lung tumour), stomach (gastric carcinoma cells;

Kinin receptor genes in cancer

TK released kinins increase vascular blood flow and promote the supply of nutrients and oxygen to the tumour. Increased vascular permeability by kinins and cellular actions of kinins via B2 and B1 receptors can aid tumour metastasis and stimulate DNA synthesis, thereby promoting cell proliferation Marceau 1995, Robert & Gulick 1989. Many tumour cells, as they proliferate and infiltrate normal adjacent tissues, chemotactically attract inflammatory cells. As observed with oesophageal carcinoma

Acknowledgements

We wish to thank the National Research Foundation (SA), the Medical Research Council (SA), and the Kaiser, International Bureau, Jülick GmbH (KFA) for financial support. We wish to acknowledge Dr. Deshandra Raidoo (Medical School, University of Natal) for his assistance in the preparation of Table 1, Table 2.

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