Cross Talk Between Kallikreins A Possible Novel Enzymatic Cascade Pathway

Interactions between serine proteases are common, and substrates of serine proteases are usually other serine proteases that are activated from an inactive precursor [66]. The involvement of serine proteases in cascade pathways is well documented. One important example is the blood coagulation cascade. Blood clots are formed by a series of zymogen activations. In this enzymatic cascade, the activated form of one factor catalyzes the activation of the next factor. Very small amounts of the initial factors are sufficient to trigger the cascade because of the catalytic nature of the process. These numerous steps yield a large amplification, thus ensuring a rapid and amplified response to trauma. A similar mechanism is involved in the dissolution of blood clots. A third important example of the coordinated action of serine proteases is the intestinal digestive enzymes. The apoptosis pathway is another important example of coordinated action of other types of proteases.

The cross-talk between kallikreins and the hypothesis that they are involved in a cascade enzymatic pathway are supported by strong, but mostly circumstantial evidence, as follows: many kallikreins are coexpressed in the same tissue (e.g., the adjacently localized kallikrein genes KLK2, KLK3, KLK4, and KLK5 are all highly expressed in the prostate); some kallikreins have the ability to activate each other and the ability of other serine proteases to activate kallikreins (see following); the common patterns of steroid hormonal regulation; the parallel pattern of differential expression of many kallikreins in different malignancies (e.g., at least seven kallikrein genes are up-regulated in ovarian cancer, and at least seven kallikreins are down-regulated in breast cancer); and serine proteases commonly use other serine proteases as substrates.

Recent experiments have shown that hK3 can be activated by hK15 [161]. hK4 has also recently been shown to activate hK3 and does so much more efficiently compared to hK2 [106]. hK5 is predicted to be able to activate hK7 in the skin [103]. The activation of hK3 by hK2 is also possible. Although Takayama et al., reported the ability of hK2 to activate hK3 [162], Denmeade et al. reported the opposite [105] and hypothesized that additional proteases may be required. It will be interesting to study all possible combinations of interactions among kallikreins, especially those with expression in the same tissues. Bhoola et al. have recently provided strong evidence of the involvement of a "kallikrein cascade'' in initiating and maintaining systemic inflammatory responses and immune-modulated disorders [163].

Kallikreins might also be involved in cascade reactions involving nonkal-likrein substrates. This is evident from the reported, but questionable, ability of hK3 to digest insulin-like growth factor-binding protein [164] and to inactivate parathyroid hormone-related protein [165]. Similar properties were reported for rodent kallikreins. There is also experimental evidence that hK2 and hK4 can activate the pro-form of another serine protease, the urokinase-type plasminogen activator [106, 125]. As mentioned above, other serine proteases, such as enterokinase and trypsin, are predicted to be able to activate many kallikreins. Furthermore, hK4 can degrade prostatic acid phosphatase in seminal plasma; hK7 can degrade the alpha chain of native human fibrinogen, and it is hypothesized that it is involved in an apoptotic-like mechanism that leads to skin desquamation [166]. A proposed model for the involvement of kallikreins in a cascade-like reaction and its association to the pathogenesis of ovarian cancer has recently been published [167].

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