Kallikrein-related peptidases: proteolysis and signaling in cancer, the new frontier

Abstract

The exact mechanism(s) by which kallikrein-related peptidases (KLKs) function, their levels of activity and their potential endogenous targets in vivo have only recently begun to be revealed. Our group and others have shown that KLKs can have hormonal properties by signaling via proteinase-activated receptors (PARs), a family of G-protein-coupled receptors. Signals by PAR(1), PAR(2), and PAR(4) can regulate calcium release or mitogen-activated protein kinase activation and lead to platelet aggregation, vascular relaxation, cell proliferation, cytokine release, and inflammation. We have further documented the presence of active KLK6 and 10 (by activity-based ELISA or proteomics) and the presence of proteinase inhibitors, such as alpha(1)-antitrypsin, in cancer-derived fluids. We suggest that tumors and inflamed tissues can release active KLKs, which are under tight regulation by proteinase inhibitors. These enzymes can potentially control cell/tissue behavior by regulating PAR activation in specific settings and disease stages.

Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance

“…PARs, a G-protein-coupled cell surface receptor subfamily (PAR1 -4), are activated through a cleavage, mediated exclusively by serine proteases with trypsin-like activity, within their N-terminus extracellular domain (Adams et al , 2011 ). Apart from their physiological roles, PARs can intervene in cancer-associated molecular cascades affecting cell proliferation and migration (Hollenberg et al , 2008 ;Oikonomopoulou et al , 2010b ). Given that IGFBPs and PARs are well-documented substrates of KLKs, an abnormal Kwiatkowski et al , 1998 ;Magklara et al , 1999 ;Nam et al , 2000 ;Steuber et al , 2007 PSA/KLK3 Screening; diagnosis; treatment monitoring; unfavorable prognosis Stephan et al , 2007 ;Lilja et al , 2008 ;Ulmert et al , 2009 ;Avgeris et al , 2010 KLK4 Unfavorable prognosis Avgeris et al , 2011b KLK5 Favorable prognosis Yousef et al , 2002b ;Korbakis et al , 2009 KLK11 Diagnosis; favorable prognosis Diamandis et al , 2002 ;Nakamura et al , 2003a,b ;Bi et al , 2010 KLK14 Unfavorable prognosis Yousef et al , 2003e ;Rabien et al , 2008 KLK15 Unfavorable prognosis Mavridis et al , 2010a ;Rabien et al , 2010 Breast cancer PSA/KLK3 Diagnosis; treatment response; favorable prognosis Yu et al , 1998 ;Foekens et al , 1999 ;Black et al , 2000 ;Sauter et al , 2004a Kim et al , 2001 ;Diamandis et al , 2003a ;Dong et al , 2003 ;Yousef et al , 2003b ;Oikonomopoulou et al , 2008b ;Dorn et al , 2011a,b KLK6 Diagnosis; unfavorable prognosis Diamandis et al , 2000…”

Kallikrein-related Peptidase 12 Hydrolyzes Matricellular Proteins of the CCN Family and Modifies Interactions of CCN1 and CCN5 with Growth Factors

“…In particular, numerous clinical studies have linked the differential expression signatures of KLK genes and proteins to their potential roles as cancer biomarkers (11). Kallikrein-related peptidases may be involved in different stages of cancer growth and progression including cell growth and survival, differentiation, remodeling of extracellular matrix, invasion, angiogenesis, and metastasis (4,10,12).…”

The 3rd International Symposium on Kallikreins and Kallikrein-Related Peptidases

“…Katerina Oikonomopoulou, recipient of the 'E.K. Frey-E. Werle Young Investigator Award 2009', demonstrated in cell model systems that KLK5, -6, and -14 can activate PAR1, -2, and -4 to different extents (reviewed in Oikonomopoulou et al, 2010b). Together with independent work by other groups, these results suggest that some KLK proteases could be major modulators of PAR-mediated signaling in inflammatory diseases and/or cancer.…”