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Molecular Oncology Research Institute (MORI)

Kuliopulos Laboratory

Athan Kuliopulis, MD, PhD, Principal Investigator, MORI at Tufts Medical Center&Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors that play critical roles in thrombosis, inflammation, and vascular biology. The PARs are cleaved by thrombin and other proteases at a specific peptide bond to expose a new N-terminus that binds to the body of the receptor in an unusual intramolecular mode. A major interest of our research group is to study the molecular mechanism of protease activation of the PARs and the subsequent signaling in vascular cells and in cancer.

Protease-Activated Receptors in Inflammation and Vascular Biology

Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors that play critical roles in thrombosis, inflammation, and vascular biologyThe PARs are cleaved by thrombin and other proteases at a specific peptide bond to expose a new N-terminus that binds to the body of the receptor in an unusual intramolecular mode. A major interest of our research group is to study the molecular mechanism of protease activation of the PARs and the subsequent signaling in vascular cells and in cancer.

PARs and Thrombosis

Thrombosis associated with the pathophysiological activation of platelets and vascular cells has brought thrombin and its receptors to the forefront of cardiovascular medicine. Protease signaling through the protease-activated receptors (PARs) has been shown to influence a wide range of physiological responses including platelet activation, intimal hyperplasia, inflammation, and maintenance of vascular tone and barrier function.

Figure 1. The figure illustrates interactions with PARs and several of the physiological responses to the interaction.

Pepducins as Novel Cell-Penetrating Intracellular Agonists and Antagonists of G Protein-Coupled Receptors

We have established a new technology based on cell-penetrating peptides known as pepducins as a novel approach of activating or inhibiting signaling between selected receptors and G proteins. These cell-penetrating pepducins are powerful tools to evaluate PARs, chemokines, and other receptors as potential therapeutic targets in both in vitro and mouse model systems.

Figure 2. A model of pepducin-mediated effects is shown.

Athan Kuliopulos, MD, PhD
Principal Investigator 

Rajashree Rana, PhD
Post-doctoral Fellow

Travis Barr, PhD
Post-doctoral Fellow

Emily Michael
Student

Andrew Shearer
Student

View all publications via PubMed

Mouse matrix metalloprotease-1a (Mmp1a) gives new insight into MMP function.Foley CJ, Kuliopulos A. J Cell Physiol. 2014 Dec;229(12):1875-80 [PubMed - indexed for MEDLINE] Free PMC Article

Noncanonical matrix metalloprotease-1-protease-activated receptor-1 signaling triggers vascular smooth muscle cell dedifferentiation and arterial stenosis. Austin KM, Nguyen N, Javid G, Covic L, Kuliopulos A. J Biol Chem. 2013 Aug 9;288(32):23105-15.  Free PMC Article

Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis. Foley CJ, Fanjul-Fernández M, Bohm A, Nguyen N, Agarwal A, Austin K, Koukos G, Covic L, López-Otín C, Kuliopulos A. Oncogene. 2014 Apr 24;33(17):2264-72.  Free PMC Article

Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer. Kaimal R, Aljumaily R, Tressel SL, Pradhan RV, Covic L, Kuliopulos A, Zarwan C, Kim YB, Sharifi S, Agarwal A. Cancer Res. 2013 Apr 15;73(8):2457-67.  Free PMC Article

Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis. Michael ES, Kuliopulos A, Covic L, Steer ML, Perides G. Am J Physiol Gastrointest Liver Physiol. 2013 Mar 1;304(5):G516-26.  Free PMC Article

Matrix metalloproteases and PAR1 activation. Austin KM, Covic L, Kuliopulos A. Blood. 2013 Jan 17;121(3):431-9. doi: 10.1182/blood-2012-09-355958.  Free PMC Article

Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin. Zhang P, Gruber A, Kasuda S, Kimmelstiel C, O'Callaghan K, Cox DH, Bohm A, Baleja JD, Covic L, Kuliopulos A. Circulation. 2012 Jul 3;126(1):83-91.  Free PMC Article

Matrix metalloprotease-1a promotes tumorigenesis and metastasis. Foley CJ, Luo C, O'Callaghan K, Hinds PW, Covic L, Kuliopulos A. J Biol Chem. 2012 Jul 13;287(29):24330-8. Free PMC Article

Turning receptors on and off with intracellular pepducins: new insights into G-protein-coupled receptor drug development. O'Callaghan K, Kuliopulos A, Covic L. J Biol Chem. 2012 Apr 13;287(16):12787-96.  Free PMC Article

O'Callaghan K, Lee L, Nguyen N, Hsieh MY, Kaneider NC, Klein AK, Sprague K, Van Etten RA, Kuliopulos A, Covic L. 2012. Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia. Blood. 119(7): 1717-25. Abstract

Sevigny LM, Austin KM, Zhang P, Kasuda S, Koukos G, Sharifi S, Covic L, Kuliopulos A. 2011. Protease-activated receptor-2 modulates protease-activated receptor-1-driven neointimal hyperplasia. Arterioscler Thromb Vasc Biol. 12: e100-6. Abstract

Sevigny LM, Zhang P, Bohm A, Lazarides K, Perides G, Covic L, Kuliopulos A. 2011. Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. Proc Natl Acad Sci U S A. 108(20): 8491-6. Abstract

Tressel SL, Kaneider NC, Kasuda S, Foley C, Koukos G, Austin K, Agarwal A, Covic L, Opal SM, Kuliopulos A. 2011. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol Med. 3(7): 370-84. Abstract

Kimmelstiel C, Zhang P, Kapur NK, Weintraub A, Krishnamurthy B, Castaneda V, Covic L, Kuliopulos A. 2011. Bivalirudin Is a dual inhibitor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention. Circ Cardiovasc Interv. 4: 171-179. Abstract

Tressel SL, Koukos G, Tchernychev B, Jacques SL, Covic L, Kuliopulos A. 2011. Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models. Methods Mol Biol. 683: 259-275. Abstract

Agarwal A, Tressel SL, Kaimal R, Balla M, Lam FH, Covic L, Kuliopulos A. 2010. Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: Implications for antiangiogenic therapy. Cancer Res. 70: 5880-5890. Abstract

Trivedi V, Boire A, Tchernychev B, Kaneider NC, Leger AJ, O'Callaghan K, Covic L, Kuliopulos A. 2009. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell 137: 332-343. Abstract

Kaneider NC, Leger AJ, Agarwal A, Nguyen N, Perides G, Derian C, Covic L, Kuliopulos A. 2007. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nat Immunol. 8: 1303-1312. Abstract

Kaneider NC, Leger AJ, Kuliopulos A. 2006. Therapeutic targeting of molecules involved in leukocyte-endothelial cell interactions. FEBS J. 273: 4416-4424. Abstract

Leger AJ, Jacques SL, Badar J, Kaneider NC, Derian CK, Andrade-Gordon P, Covic L, Kuliopulos A. 2006. Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation 113: 1244-1254. Abstract

Kaneider NC, Agarwal A, Leger AJ, Kuliopulos A. 2005. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nat Med. 11: 661-665. Abstract

Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. 2005. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120: 303-313. Abstract