Role of Protein C Inhibitor and Tissue Factor in Fertilization

Fernández, José A.; Heeb, Mary J.

doi:10.1055/s-2006-958457

Cited by 9 publications

(5 citation statements)

References 58 publications

(95 reference statements)

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“…In the case of seminal plasma, additional evidence reinforcing the idea of proteolytic cascades comes from the striking overlap between regulatory components of blood and seminal homeostasis (10,(42)(43)(44)(45). More recently, a number of well known components of the blood coagulation and fibrinolysis systems, including PCI, tissue type and urokinase type plasminogen activator, tissue factor, tissue factor pathway inhibitor, FIGURE 5.…”

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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“…For example, the serine protease plasmin (the activated form of plasminogen) is able to activate KLK11 in vitro (Luo et al, 2006). In addition to the proteins mentioned above, many of which are also expressed as blood plasma proteins, classic hemostatic factors may also contribute to seminal clotting and liquefaction (Lwaleed et al, 2004, 2005, 2007), including a major role for tissue factor (TF; thromboplastin) (Lwaleed et al, 2006; Fernández and Heeb, 2007). Consistent with an important role of TF in seminal fluid, levels of this protein are much higher in semen (average of 21 ng/ml; Fernández and Heeb, 2007) than in blood (average of 85 pg/ml; Fernández et al, 1997).…”

Section: Functions Of Seminal Fluid Proteases and Their Inhibitorsmentioning

confidence: 99%

Risky circuitry? psychosocial risk factors and neural circuits in the development and persistence of eating disorders. A commentary on keel & forney and friederich et al.

Walsh

2013

Intl J Eating Disorders

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“…Given the overlapping regulatory components of the seminal and blood homeostasis, this emerging evidence suggests that analogous to fibrinolysis, semen liquefaction is regulated through highly orchestrated proteolytic cascades (7,10,31,47,48).…”

Section: Discussionmentioning

confidence: 99%

Major Role of Human KLK14 in Seminal Clot Liquefaction

Emami

Deperthes

Malm

et al. 2008

Journal of Biological Chemistry

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Liquefaction of human semen involves proteolytic degradation of the seminal coagulum and release of motile spermatozoa. Several members of human kallikrein-related peptidases (KLKs) have been implicated in semen liquefaction, functioning through highly regulated proteolytic cascades. Among these, KLK3 (also known as prostate-specific antigen) is the main executor enzyme responsible for processing of the primary components of semen coagulum, semenogelins I and II. We have recently identified KLK14 as a potential activator of KLK3 and other KLKs. This study aims to elucidate the cascade-mediated role of KLK14 ex vivo. KLK14 expression was significantly lower (p ‫؍‬ 0.0252) in individuals with clinically delayed liquefaction. Concordantly, KLK14 expression was significantly (p ‫؍‬ 0.0478) lower in asthenospermic cases. Specific inhibition of KLK14 activity by the synthetic inhibitor ACT G9 resulted in a significant delay in semen liquefaction, a drop in the "early" (30 min postejaculation) "chymotrypsin-like" and KLK1 activity, and an increase in the "late" (90 min postejaculation) chymotrypsinlike activity. Conversely, the addition of recombinant active KLK14 facilitated the liquefaction process, augmented the early chymotrypsin-like activity, and lowered late chymotrypsin-like activity. Given that the observed chymotrypsin-like activity was almost completely attributed to KLK3 activity, KLK3 seems to be regulated bidirectionally. Accordingly, a higher level of KLK3 fragmentation was observed in KLK14-induced coagula, suggesting an inactivation mechanism via internal cleavage. Finally, semenogelins I and II were directly cleaved by KLK14. Semenogelins were also able to reverse KLK14 inhibition by Zn 2؉ , providing a novel regulatory mechanism for KLK14 activity. Our results show that KLK14 exerts a significant and dose-dependent effect in the process of semen liquefaction.

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Role of Protein C Inhibitor and Tissue Factor in Fertilization

Cited by 9 publications

References 58 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

Risky circuitry? psychosocial risk factors and neural circuits in the development and persistence of eating disorders. A commentary on keel & forney and friederich et al.

Major Role of Human KLK14 in Seminal Clot Liquefaction

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