Tissue Kallikrein of Human Seminal Plasma is Secreted by the Prostate Gland

Fink, Edwin; Schill, Wolf‐Bernhard; Fiedler, F.; Krassnigg, F.; Geiger, Reinhard; Shimamoto, Kazuaki

doi:10.1515/bchm3.1985.366.2.917

Cited by 66 publications

(32 citation statements)

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“…Given the substrate overlap between KLK1 and other KLKs of the skin proteolytic cascade, it is conceivable that KLK1 functions through a common proteolytic network. In seminal plasma, along with other seminal KLKs, KLK1 is secreted from the prostate gland and is known to complex with PCI (58,59). PCI has been shown to complex with several other seminal KLKs, including the two prominent members of the proteolytic cascade, KLK2 and -3 (59, 60).…”

Section: Discussionmentioning

confidence: 99%

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Emami¹,

Diamandis²

2008

Journal of Biological Chemistry

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Human kallikrein-related peptidases (KLKs) are a family of 15 serine proteases mainly known for their biomarker utility in various neoplastic and non-neoplastic diseases. Despite significant progress in understanding their clinical application, little is known about the activation mechanism(s) of this important family of enzymes. Emerging evidence indicates that KLKs are activated in a stepwise manner, which is a characteristic of proteolytic cascades. Thus far, KLK cascades have been implicated in semen liquefaction and skin desquamation. Many members of the KLK family have been reported to be active in seminal plasma and/or skin, suggesting their involvement in common proteolytic cascades. KLK14, in particular, is highly active and has recently been proposed as one of the key trypsin-like proteases involved in skin desquamation. This study aims to elucidate a probable cascade-mediated role of KLK14 by 1) examining KLK14-mediated cleavage of a heptapeptide library encompassing activation sites of the 15 KLKs and 2) verifying activation of certain candidate downstream targets of KLK14 (i.e. pro-KLK1, -KLK3, and -KLK11). Heptapeptides encompassing activation motifs of KLK2, -3, -5, and -11 were cleaved with a high (>85%) cleavage efficiency. Activation of these candidates was confirmed using full-length recombinant proteins. Pro-KLK11, -KLK3, and -KLK1 were rapidly activated in a concentration-dependent manner. Pro-KLK3 regulation was bidirectional because activation was followed by inactivation via internal cleavage of active KLK3. We are proposing a putative cascade model, operating through multiple KLKs. Identification of novel members of such proteolytic cascades will aid in further defining mechanisms involved in seminal/skin homeostasis.Proteases are a major group of enzymes participating in a multitude of physiological processes, including coagulation, apoptosis, and immune responses (1). Due to the irreversible nature of proteolytic activation, proteases often remain as inactive zymogens in quiescent conditions. Activation is often triggered by an external stimulus and mediated by highly orchestrated cascades (2). Within a cascade, proteases function coordinately to ensure sequential activation of protease zymogens. The result is a rapid amplification of signal, in response to a minute amount of stimulus (2).Proteolytic cascades are tightly regulated through a series of highly orchestrated feedback loops, internal cleavages, and (auto)degradations. Also, inhibitors play a major role by targeting activated proteases (2). These multiple regulatory points are critical in preventing deleterious effects due to uncontrolled protease activation. Dysregulated protease activation has been implicated in several pathological conditions, such as amyloidogenesis in Alzheimer disease, intravascular coagulation in sepsis, and desquamation in various skin disorders as well as tumor metastasis, invasion, and angiogenesis in cancer (2-5).KLKs 2 belong to a subgroup of secreted serine proteases within the S1 family of clan ...

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Section: Discussionmentioning

confidence: 99%

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Emami¹,

Diamandis²

2008

Journal of Biological Chemistry

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“…Kinin determination was performed by radioimmunoassay, as described previously. 21 Finally, the MBP responses of Bk2r Ϫ/Ϫ or Bk2r ϩ/ϩ (nϭ6 per group) to acute blockade of the bradykinin B 1 receptor were assessed after 3 weeks of DOC administration by injection of the B 1 receptor antagonist AcLys[D-␤-Nal, 7 Ile 8 ]des-Arg 9 -bradykinin (3 nmol/100 g body wt IV), a generous gift from Professor Domenico Regoli (University of Sherbrooke, Canada) or vehicle. MBP was recorded under basal conditions and for 10 minutes after injection.…”

Section: Cardiovascular and Renal Effects Of Doc Enantatementioning

confidence: 99%

Enhanced Blood Pressure Sensitivity to Deoxycorticosterone in Mice With Disruption of Bradykinin B ₂ Receptor Gene

Emanueli

Fink²,

Milia³

et al. 1998

Hypertension

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Abstract-The renal kallikrein-kinin system is activated under conditions of mineralocorticoid excess. To evaluate whether endogenous kinins exert a protective role against the development of mineralocorticoid-induced hypertension, we studied the cardiovascular effects induced by long-term administration of deoxycorticosterone (DOC; 0.3 mol/g body wt SC once per week for 6 weeks) or vehicle in transgenic mice (Bk2r Ϫ/Ϫ ) lacking the bradykinin B 2 receptor gene and in wild-type controls (Bk2r ϩ/ϩ ). Under basal conditions, Bk2r Ϫ/Ϫ mice showed higher systolic blood pressure (tail-cuff plethysmography) than wild-type Bk2r ϩ/ϩ and heterozygous Bk2r ϩ/Ϫ mice (121Ϯ2 versus 114Ϯ2 and 115Ϯ2 mm Hg, respectively; PϽ0.05 for both comparisons). Heart rate was higher in Bk2r Ϫ/Ϫ and Bk2r ϩ/Ϫ than in Bk2r ϩ/ϩ (459Ϯ12 and 418Ϯ7 versus 390Ϯ7 bpm; PϽ0.05 for both comparisons). Systolic blood pressure was increased by DOC in transgenic as well as in wild-type mice, whereas no change was induced by the vehicle. The pressor response to DOC was more rapid and pronounced in Bk2r Ϫ/Ϫ than in Bk2r ϩ/ϩ and Bk2r ϩ/Ϫ (30Ϯ5 versus 15Ϯ4 and 6Ϯ3 mm Hg, respectively, at 3 weeks; PϽ0.01 for both comparisons). The difference in systolic blood pressure was consistent with that detected by direct intra-arterial measurements of mean blood pressure. Neither DOC nor its vehicle altered heart rate or gain in body weight over time. Under basal conditions, urinary sodium excretion did not differ between strains. During DOC administration, cumulative urinary sodium excretion was lower in Bk2r Ϫ/Ϫ than in Bk2r ϩ/ϩ (2.59Ϯ0.15 versus 3.31Ϯ0.22 mmol, respectively, during the first week; PϽ0.05). Urinary kinin excretion was increased by DOC in both Bk2r Ϫ/Ϫ (from 0.65Ϯ0.17 to 4.27Ϯ0.80 pmol/24 h; PϽ0.01) and Bk2r ϩ/ϩ (from 0.55Ϯ0.09 to 6.27Ϯ1.48 pmol/24 h; PϽ0.05). The increase in urinary kinin excretion was similar between strains. These results show that integrity of the bradykinin B 2 receptor is essential for regulation of blood pressure and heart rate under basal conditions. In addition, they indicate that activation of the kallikrein-kinin system represents a compensatory response against the development of hypertension induced by mineralocorticoid excess. (Hypertension. 1998;31:1278-1283.) Key Words: mineralocorticoids Ⅲ blood pressure Ⅲ kallikrein-kinin system K inins, the enzymatic products of kininogen cleavage by kallikrein, induce vasodilatation, diuresis, and natriuresis by promoting the release of endothelium-derived relaxing factors and prostaglandins.1-4 They act as local hormones by activating specific receptors named B 1 and B 2 , with most of the cardiovascular and renal effects being mediated by the B 2 receptor.5 It has been hypothesized that a dysfunction of the KKS, leading to unbalanced predominance of vasoconstrictor and antinatriuretic systems, may contribute to the pathogenesis of arterial hypertension. Interestingly, at variance with other models of genetic or experimental hypertension characterized by a defective renal synthesis...

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“…One possible function could be the release of kinin from kininogen. A 'true' TK able to release kallidin, and originating from the prostate, has been identified in human seminal plasma (Fink et al, 1985). Although the kallidin-releasing and guinea pig blood pressure regulating activities of gpK2 were comparatively low, due to the large amounts of this enzyme occurring in these glands it could generate significant amounts of kinin and compensate for the absence of gpK1.…”

Section: Discussionmentioning

confidence: 99%

Not More than Three Tissue Kallikreins Identified from Organs of the Guinea Pig

Fiedler¹,

Betz²,

Hinz³

et al. 1999

Biological Chemistry

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The large and varied multigene families of tissue kallikreins of rat and mouse are considered to selectively release as many bioactive peptides. In order to determine whether a similar family of enzymes is expressed in the organs of the guinea pig purification studies were performed. Tissue kallikreins from the submandibular gland, coagulating gland/prostate complex and the pancreas were separated by affinity chromatography on benzamidine-Sepharose. Amino-terminal sequences, the patterns of hydrolysis rates of a number of peptide p-nitroanilides, inactivation rates by active site-directed irreversible inhibitors, specific kininogenase activities and types of kinin released were used to probe the identity of the isolated enzymes.Guinea pig tissue kallikreins 1 and 2 have been reported previously. In the present study we have identified a third type, designated tissue kallikrein 1a because of its sequence similarity to kallikrein 1, which differs from the latter in the catalytic properties. The inferred occurrence of not more than two or three independent tissue kallikrein genes in the guinea pig contrasts with the varied family of enzymes expressed by the large number of such genes present in rats and mice. Expression in the guinea pig (and also in humans) of only a small number of tissue kallikreins makes specific processing of a multitude of biologically active peptides by such enzymes unlikely.

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Tissue Kallikrein of Human Seminal Plasma is Secreted by the Prostate Gland

Abstract: Enzyme:Tissue kallikrein (EC 3.4.21.35). Abbreviations:Ac-Phe-Arg-OEt = Acetylphenylalanyl-arginine ethyl ester; HUK = human urinary tissue kallikrein. * Parts of this publication were presented at

Cited by 66 publications

References 19 publications

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Enhanced Blood Pressure Sensitivity to Deoxycorticosterone in Mice With Disruption of Bradykinin B ₂ Receptor Gene

Not More than Three Tissue Kallikreins Identified from Organs of the Guinea Pig

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Tissue Kallikrein of Human Seminal Plasma is Secreted by the Prostate Gland

Abstract: Enzyme:Tissue kallikrein (EC 3.4.21.35). Abbreviations:Ac-Phe-Arg-OEt = Acetylphenylalanyl-arginine ethyl ester; HUK = human urinary tissue kallikrein. * Parts of this publication were presented at

Cited by 66 publications

References 19 publications

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Enhanced Blood Pressure Sensitivity to Deoxycorticosterone in Mice With Disruption of Bradykinin B 2 Receptor Gene

Not More than Three Tissue Kallikreins Identified from Organs of the Guinea Pig

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Enhanced Blood Pressure Sensitivity to Deoxycorticosterone in Mice With Disruption of Bradykinin B ₂ Receptor Gene