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AACR2006-1686P Funding Proteinases and Inflammation Network Group grant Kallikrein 14 Signalling through Proteinase-Activated Receptors CIHR operating grant 1,2 3,4 3,4 3,4 5 Alberta Heritage Foundation for Katerina Oikonomopoulou , Kristina K. Hansen , Mahmoud Saifeddine , Illa Tea , Patricia Andrade-Gordon , Medical Research Graeme S. Cottrell6, Nigel W. Bunnett6, Nathalie Vergnolle3, Eleftherios P. Diamandis1,2 and Morley D. Hollenberg3,4 NSERC / CRSNG 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto; 2Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto; 3Department of Pharmacology & Therapeutics, and 4Department of Medicine, University of Calgary, Calgary; 5Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania, 6Departments of Surgery and Physiology, University of California, San Francisco Kallikrein 14 can selectively disarm PAR (lower concentrations), OVERVIEW Figure 1: Mechanism of PAR activation (activation by proteolysis) 2. Kallikrein 14 can selectively disarm PAR1 (lower concentrations), 2+ Proteinase-activated receptors (PARs): a family of G-protein coupled receptors activated by serine proteinase cleavage site whilst activating PARs 2 and 4; Ca in HEK cells proteinases via a proteolytically revealed ‘tethered ligand’ (Fig. 1). Four family members (Fig. 2); PARs N PAR disarming 1, 2 and 4 signal to cells. N PAR1 dis-arming1 vs. activation Selective activation of PAR4 vs. PARs 1, 2 Human kallikreins (hKs): A 15-member family of secreted serine proteinases implicated in tumour 1 cm Thrombin 1 cm 2 min 2 min TFLLR-NH2 progression and cell survival (Fig. 4). (selective desensitization hK14: a tryptic kallikrein; wide tissue distribution, implicated in breast and ovarian cancer (Fig. 5 and 6). of PAR1) The mechanism of kallikrein action is not yet known: Although some targets have been identified (e.g. extracellular matrix; pro-UPA), the mechanism whereby kallikreins regulate tissue function is not hK14, 5 U/ml AYPGKF-NH2 200 µM, selective known. SFLLR-NH2 desensitization of C C 200µM, selective PAR desensitization of 4 We hypothesized that hK14, as a prototype kallikrein, modulates cell survival and tumour growth by signalling hK14, PARs 1, 2 regulating (activating or inactivating/dis-arming) proteinase-activated receptor (PAR) signalling. PAR1 Main conclusions: hK14 activated PAR in cultured cells (Ca++ signalling) and caused PAR -mediated 2 2 Proteinase Figure 2: The PAR family Figure 3: response Ca % relaxation of rat and murine vascular tissue. In addition, hK14 had a dual action on PAR1, depending on cleavage/activation site the enzyme concentration (principally dis-arming). In human platelets, hK14 was able to cause 4 PARs are known in rodents and humans 2+ proteinase cleavage site Hirudin-like 3. Kallikrein 14 can cause platelet aggregation and Ca signalling aggregation by activating PAR4 whilst dis-arming PAR1. Major Activating Receptor Some Disarming proteinases binding domain proteinases through PAR4 in isolated platelets Significance of study: In the setting of human tumours, known to be platelet-rich, hK14 would trigger PAR : …ESKATNATLDPR SFLLRN PN DKYEPFWEDEEKNES … 1 100 platelet aggregation and the preferential release of platelet endostatin rather than VEGF via PAR (PNAS PAR1 Thrombin Trypsin, Cathepsin G Rat Platelet (PAR ) Human Platelet (PARs 1 and 4) signalling 4 PAR : …GTNRSSKGR SLIGKV DG… 4 2005;102(1):216-20). Also, by targeting PAR . and/or PAR , hK14 could participate in tumour growth and 2 Aggregation 2 4 PAR Trypsin, Tryptase Elastase 1 cm 2 PAR3: …NDTNNLAKPTLPIK TFRGAP PNS FEEEP FSALE… survival, as well as in the inflammatory responses during cancer progression. 2 min PAR4: …LPAPR GYPGQV CANDSDTLELPDSS… PAR3 Thrombin Cathepsin G Thrombin, 1 U/ml Figure 4: Human Kallikreins Tethered ligand Trypsin, 10 U/ml PAR4 Thrombin Unknown; Kallikreins ? Note: Hirudin-like binding domain hK14, 20 U/ml hK14, 20 U/ml Kallikrein locus Characteristics of the kallikrein family: 50 AYPGKF-NH2 unique to PAR1 (and PAR3) 200 µM, selective Steinhoff M. et al., Endocr Rev. 2005;26:1-43 hK6, 20 U/ml TFLLR-NH2 desensitization of ¾The largest cluster of continuous 10 µM, selective PAR proteinases of any kind hK5, 20 U/ml desensitization of 4 PAR1 ¾The largest group of serine proteinases Materials and Methods ¾Trypsin or Chymotrypsin-like activity Calcium signalling Bioassays ACPT KLK1 KLK15 KLK3 KLK2 KLK4 KLK5 KLK6 KLK7 KLK8 KLK9 KLK10 KLK11 KLK12 KLK13 KLK14 Sinclec-9 Fluo-3 Borgono CA. et al, Nat Rev Cancer. 2004;4:876-90 of lightMax Transmission % 0 4.8 4.6 6.2 5.8 5.8 4.4 9.5 10.5 6.5 5.7 7.1 5.4 5.3 5.8 5.4 ¾ Calcium signalling assay in human ¾ Aorta endothelium: Contraction / relaxation response Ca % 8.9 6.3 -O OO Borgono CA. et al, Mol Cancer Res. 2004;2:257-80 HEK cells (PARs 1 and 2 / PAR ) (PAR ) 4 Cl Cl 2 and rat KNRK (PAR2) 4. Kallikreins can cause aorta relaxation, 5. hK14 can cause ¾ Human (PAR1 and PAR4) and Rat (PAR4) 4. 5. prepro-hK14 2+ OCH2 CH2 O ¾ Method: Incubate cells with Ca N N ++ platelets: Aggregation / Ca assays mediated through PAR2 activation murine paw inflammation NC -O CCO- 18 6 227 251 aa indicator (Fluo-3) Æ examine for -O 2 C CO 2 - 2 2 27.5 kDa cross-desensitization of PARs, ¾ Inflammation Rat 0.6 signal upon secretion using PAR-activating peptides, agonists and antagonists: 0.5 Kawabata A. et al., JPET 1999;288: 358-70 peptide Figure 5: TFLLR-NH2 - selective desensitization of PAR1 Control Ach SFLLR-NH - selective desensitization of PARs 1, 2 0.4 2 Hollenberg MD. et al., Can J Physiol Pharmacol. 1997;75:832-41 response pro-hK14 Kallikreins are AYPGKF-NH - selective desensitization of PAR 0.3 18 N 6 227 C 2 4 Hollenberg MD. et al., Can J Physiol Pharmacol. 2001;79:439-42 1 g Trypsin and / or Thrombin 0.2 233 aa secreted enzymes Phenylephrine and Acetylcholine Vergnolle N. et al., Br J Pharmacol. 1999;127:1083-90 5 min Paw diameter (mm) 0.1 L-NAME - inhibitor of NOS-mediated aorta relaxation Mouse Paw diameter (mm) e.g. hK14 ∆ upon activation L-NAME 0.1mM, Inhibitor 0.0 activation 0.1 g of NOS-mediated relaxation in in Control Ach m peptide 5 min 0 m mature Results response Phenylephrine 1 µM 30 6 Time after intraplantar injections (min) (active) hK14 6 N 227 C Acetylcholine 10 µM Active hK14 (n=5) Heat-Inactivated hK14 (n=5) 227 aa 1. hK14 can cleave within synthetic PAR 1, 2 and 4 peptides hK14, 3 U/ml hK5, 5 U/ml hK6, 3 U/ml (designed based on the cleavage/activation motifs; Fig.3) Figure 6: Kallikrein expression Tissue Expression of Kallikreins (RT-PCR) Kallikreins and cancer Tethered ligand sequence Conclusions; Kallikreins can regulate PAR activity N Salivary glands CNS KLK1, KLK4, KLK5, KLK6, hK KLK1, KLK3, KLK2, KLK5, KLK6, Receptor Trypsin (3.5 U/ml) hK14 (4.3 U/ml) KLK7, KLK8, KLK9, KLKL10, ¾PSA/hK3 is utilized to monitor prostate N KLK7, KLK9, KLK10, KLK11, KLK12, KLK11, KLK12, KLK14 KLK13, KLK15 cancer patients hPAR NATLDPR / SFLLRNPNDKYE NATLDPR / SF / LLR / NPNDKYE Trachea 1 hK Thyroid KLK3, KLK5, KLK6, KLK9, KLK10, KLK11, KLK12, KLK13 KLK3, KLK2, KLK4, KLK5, KLK7, KLK11, ¾hK6 (Zyme / proteinase M / Neurosin), hK10 KLK12, KLK13, KLK14, KLK15 hPAR GTNRSSKGR / SLIGK / V / DGTSH VTGK / GVT GTNRSSKGR / SLIGK / VDGTSHVTGK / GVT Thymus Lung (NES1), hK11, hK8, hK5 and hK14 may 2 KLK5, KLK6, KLK7, KLK9, KLK3, KLK10, KLK11, KLK12, KLK13 hK KLK11, KLK12, KLK13, KLK14 PAR C N hK 2 Breast represent novel ovarian cancer biomarkers Kidney hPAR GDDSTPSILPAPR / GYPGQV G / DDSTPSILPAPR / GY / PGQV KLK1, KLK3, KLK2 KLK4, KLK5, KLK6 KLK7, 4 2+ KLK1, KLK6 KLK7, KLKL9, KLK10, KLK11, KLK12, KLK13, KLK14 Ca release KLK14, KLK15 ¾hK11 may represent a novel prostate cancer C Heart Vasorelaxation Colon KLK11, KLK13 rPAR2 GPNSKGR / SLIGRLDTPY / G / GC GPNSKGR / SLIGRLDTPY / GG / C KLK4, KLK10, KLK12, biomarker KLK13, KLK14, KLK15 Skin rPAR L / NESK / SPDKPNPR / GFPGKP LNESKSPDKPNPR / GFPGK / P PAR1 C Pancreas KLK5, KLK7, KLK8, KLK9, KLK11 Ovary ¾hK5 and hK14 may represent novel breast 4 KLK1, KLK10, KLK12 KLK7, KLK8, 2+ PAR4 KLK9, KLK10 cancer biomarkers Ca release Possible role in carcinogenesis: 2+ Uterus Ca release KLK1, KLK4, KLK6, KLK7, Testis Only the intact ligand sequences, that would remain tethered to the KLK10, KLK11, KLK12, KLK14 KLK1, KLK4, KLK5, KLK6, ¾hKs can cleave several pro-uPA, GFs and Human Platelet KLK7, KLK9, KLK10, ¾ Angiogenesis ¾ Tumour growth KLK12, KLK13, KLK15 receptor, would result in signalling. Other potential cleavage sites Aggregation Human and Rat Platelet Prostate ECM proteins KLK1, KLK3, KLK2, KLK4, KLK5, KLK9, Aggregation KLK10, KLK11, KLK12, KLK13, KLK15 would dis-arm the receptor, preventing receptor activation. Oikonomopoulou K. et al., Biol Chem 2006 ¾ Inflammation ¾ Tumour survival.
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