Interdependence of kallikrein-related peptidases in proteolytic networks

Abstract

Human kallikrein-related peptidases (KLKs) are 15 homologous serine proteases involved in several (patho)physiological processes, including cancer. Secreted as precursors, they are activated upon proteolytic release of a short propeptide. We searched for interconnection of KLKs within extracellular proteolytic networks leading to activation of protease zymogens and found that (i) pro-KLK activation by other KLKs is scarce, with the exception of pro-KLK11, which is efficiently activated by KLK4 and 5; (ii) pro-KLK4 is activated by matrix metalloproteinase 3; and (iii) trypsinlike KLKs efficiently activate the serine protease urokinase. Our observations provide new insights into the regulation of these important tumor-associated proteases.

Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance

“…For instance, KLK4 has been shown to degrade fibrinogen [37] and FN, VN (unpublished data), KLK5 and KLK6 degrade FN, VN, Col I, Col IV, and KLK7 degrades FN [15]. Our KLK4-7 data indicate that, as with MMPs [38], a more complex regulatory event influences integrin levels and binding capacity to specific ECM proteins (VN/FN), both key elements in cancer metastasis. KLK4-7-expression in EOC cells did not alter attachment to Col I and Col IV, but attachment decreased to FN and VN.…”

Unleashing the therapeutic potential of human kallikrein-related serine proteases

“…Our understanding of the complex proteolytic networks that govern KLK activity in vivo is far from complete. KLKs do not work in isolation, but rather as individual parts of a complicated network of proteases, substrates and endogenous inhibitors [214][215][216] . In such a complex context, delineating the overlapping, synergistic and opposing activities of an individual KLK is challenging.…”

Doxycycline Indirectly Inhibits Proteolytic Activation of Tryptic Kallikrein-Related Peptidases and Activation of Cathelicidin

“…Activation entails either autoactivation and/or activation by other KLKs in a cascade-like manner, or removal of the profragment by enzymes such as matrix metalloproteinases (MMPs) or other endopeptidases (Ryu et al ., 2002; Lundwall and Brattsand, 2008; Sotiropoulou et al ., 2009). For example, pro-KLK4 undergoes proteolytic activation by MMP-3 and MMP-20 (Ryu et al ., 2002; Beaufort et al ., 2010; Chun et al ., 2010). Pro-KLK7 is processed by another epidermal metalloproteinase, meprin β, before activation of pro-KLK7 by tryptic enzymes (Ohler et al ., 2010).…”