Kallikrein-related peptidases (known as KLKs) constitute a single family of 15 secreted, highly conserved serine proteases with tryptic or chymotryptic activity. KLKs share a wide range of expression in different tissues; examples of KLK co-expression, are certain groups expressed in the prostate (KLKs 2-4, 11, and 15), skin (KLKs 1, 4-11, 13, and 14), breast (KLKs 5, 6, 10, and 13), and the central nervous system (KLKs 6-9, 14). Aberrant regulation of KLKs has been associated with several diseases such as hypertension, renal dysfunction, skin desquamation, inflammation, neurodegeneration, and tumor-promotion or -inhibition. However, despite their widespread expression in diseased tissues, the exact mechanisms by which this enzyme family regulates cellular function are not clear and their potential endogenous targets in vivo are only beginning to be revealed. Tumor marker prostate-specific antigen (PSA/KLK3), for example, is the most widely known KLK due to its application in diagnosis and monitoring of prostate cancer, nevertheless the biological role of this enzyme in cancer progression is unclear. Accumulating evidences suggest that KLKs signal via proteinase activated receptors (PARs), a family which has been implicated in several pathways of cell signaling. PARs are G-protein-coupled receptors with seven transmembrane domains, which are activated by a unique mechanism dependent on proteolytic cleavage. KLKs can regulate multiple signaling pathways triggered by PARs 1, 2, and 4, resulting in calcium release, platelet aggregation and vascular relaxation, and they can cause murine inflammation. KLK-derived regulation of PARs would be critical for many pathological conditions affecting different tissues, where distinct groups of KLKs are expressed. Via the PARs, KLKs can regulate processes including cell migration, inflammation, nociception, as well as angiogenesis, cell apoptosis, adhesion, proliferation, metastasis, and invasion. Therefore, the kallikrein-PAR axis may be considered as an attractive target for drug development.
Kallikrein Protease Activated Receptor (PAR) Axis: An Attractive Target for Drug Development / Caliendo, Giuseppe; Santagada, Vincenzo; Perissutti, Elisa; Severino, Beatrice; Fiorino, Ferdinando; Frecentese, Francesco; Juliano, L.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 55:15(2012), pp. 6669-6686. [10.1021/jm300407t]
Kallikrein Protease Activated Receptor (PAR) Axis: An Attractive Target for Drug Development
CALIENDO, GIUSEPPE;SANTAGADA, VINCENZO;PERISSUTTI, ELISA;SEVERINO, BEATRICE;FIORINO, FERDINANDO;FRECENTESE, FRANCESCO;
2012
Abstract
Kallikrein-related peptidases (known as KLKs) constitute a single family of 15 secreted, highly conserved serine proteases with tryptic or chymotryptic activity. KLKs share a wide range of expression in different tissues; examples of KLK co-expression, are certain groups expressed in the prostate (KLKs 2-4, 11, and 15), skin (KLKs 1, 4-11, 13, and 14), breast (KLKs 5, 6, 10, and 13), and the central nervous system (KLKs 6-9, 14). Aberrant regulation of KLKs has been associated with several diseases such as hypertension, renal dysfunction, skin desquamation, inflammation, neurodegeneration, and tumor-promotion or -inhibition. However, despite their widespread expression in diseased tissues, the exact mechanisms by which this enzyme family regulates cellular function are not clear and their potential endogenous targets in vivo are only beginning to be revealed. Tumor marker prostate-specific antigen (PSA/KLK3), for example, is the most widely known KLK due to its application in diagnosis and monitoring of prostate cancer, nevertheless the biological role of this enzyme in cancer progression is unclear. Accumulating evidences suggest that KLKs signal via proteinase activated receptors (PARs), a family which has been implicated in several pathways of cell signaling. PARs are G-protein-coupled receptors with seven transmembrane domains, which are activated by a unique mechanism dependent on proteolytic cleavage. KLKs can regulate multiple signaling pathways triggered by PARs 1, 2, and 4, resulting in calcium release, platelet aggregation and vascular relaxation, and they can cause murine inflammation. KLK-derived regulation of PARs would be critical for many pathological conditions affecting different tissues, where distinct groups of KLKs are expressed. Via the PARs, KLKs can regulate processes including cell migration, inflammation, nociception, as well as angiogenesis, cell apoptosis, adhesion, proliferation, metastasis, and invasion. Therefore, the kallikrein-PAR axis may be considered as an attractive target for drug development.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.