Abstract
The four PAR family members are G protein coupled receptors that are normally activated by proteolytic exposure of an occult tethered ligand. Three of the family members are thrombin receptors. The fourth (PAR2) is not activated by thrombin, but can be activated by other proteases, including trypsin, tryptase and Factor Xa. This review focuses on recent information about the manner in which signaling through these receptors is initiated and terminated, including evidence for inter- as well as intramolecular modes of activation, and continuing efforts to identify additional, biologically-relevant proteases that can activate PAR family members.
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References
Al-Ani B, Saifeddine M, Kawabata A, Hollenberg MD . 1999 Br. J. Pharmacol. 128: 1105–1113
Alm AK, Gagnemo-Persson R, Sorsa T, Sundelin J . 2000 Biochem. Biophys. Res. Commun. 275: 77–83
Andrade-Gordon P, Maryanoff BE, Derian CK, Zhang H-C, Addo MF, Darrow AL, Eckardt AJ, Hoekstra WJ, McComsey DF, Oksenberg D, Reynolds EE, Santulli RJ, Scarborough RM, Smith CE, White KB . 1999 Proc. Natl. Acad. Sci. USA 96: 12257–12262
Bahou WF, Coller BS, Potter CL, Norton KJ, Kutok JL, Goligorsky MS . 1993 J. Clin. Invest. 91: 1405–1413
Bahou WF, Kutok JL, Wong A, Potter CL, Coller BS . 1994 Blood 84: 4195–4202
Bernatowicz MS, Klimas CE, Hartl KS, Peluso M, Allegretto NJ, Seiler SM . 1996 J. Med. Chem. 39: 4879–4887
Blackhart BD, Emilsson K, Nguyen D, Teng W, Martelli AJ, Nystedt S, Sundelin J, Scarborough RM . 1996 J. Biol. Chem. 271: 16466–16471
Brass LF . 1992 J. Biol. Chem. 267: 6044–6050
Brass LF, Vassallo Jr RR, Belmonte E, Ahuja M, Cichowski K, Hoxie JA . 1992 J. Biol. Chem. 267: 13795–13798
Brass LF, Pizarro S, Ahuja M, Belmonte E, Stadel J, Hoxie JA . 1994 J. Biol. Chem. 269: 2943–2952
Böhm SK, Khitin LM, Grady EF, Aponte G, Payan DG, Bunnett NW . 1996 J. Biol. Chem. 271: 22003–22016
Camerer E, Rottingen J-A, Gjernes E, Larsen K, Skartlien AH, Iversen J-G, Prydz H . 1999 J. Biol. Chem. 274: 32225–32233
Camerer E, Huang W, Coughlin SR . 2000 Proc. Natl. Acad. Sci. USA 97: 5255–5260
Caughey GH . 1994 Am. J. Resp. Crit. Care Med. 150: s138–s142
Chao BH, Kalkunte S, Maraganore JM, Stone SR . 1992 Biochemistry 31: 6175–6178
Chen J, Ishii M, Wang L, Ishii K, Coughlin SR . 1994 J. Biol. Chem. 269: 16041–16045
Chen XL, Earley K, Luo WP, Lin SH, Schilling WP . 1996 Biochem. J. 314: 603–611
Cheung WM, D'Andrea MR, Andrade-Gordon P, Damiano BP . 1999 Arterioscler. Thromb. Vasc. Biol. 19: 3014–3024
Connolly AJ, Ishihara H, Kahn ML, Farese Jr RV, Coughlin SR . 1996 Nature 381: 516–519
Corvera CU, Dery O, McConalogue K, Bohm SK, Khitin LM, Caughey GH, Payan DG, Bunnett NW . 1997 J. Clin. Invest. 100: 1383–1393
Coughlin SR . 2000 Nature 407: 258–264
D'Andrea MR, Derian CK, Leturcq D, Baker SM, Brunmark A, Ling P, Darrow AL, Santulli RJ, Brass LF, Andrade-Gordon P . 1998 J. Histochem. Cytochem. 46: 157–164
Damiano BP, Cheung WM, Santulli RJ, Fung-Leung WP, Ngo K, Ye RD, Darrow AL, Derian CK, De Garavilla L, Andrade-Gordon P . 1999 J. Pharmacol. Exp. Ther. 288: 671–678
Darrow AL, Fung-Leung WP, Ye RD, Santulli RJ, Cheung WM, Derian CK, Burns CL, Damiano BP, Zhou LB, Keenan CM, Peterson PA, Andrade-Gordon P . 1996 Thromb. Haemost. 76: 860–866
Detwiler TC, Feinman RD . 1973a Biochemistry 12: 282–289
Detwiler TC, Feinman RD . 1973b Biochemistry 12: 2462–2468
Doorbar J, Winter G . 1994 J. Mol. Biol. 244: 361–369
Déry O, Corvera CU, Steinhoff M, Bunnett NW . 1998 Am. J. Physiol. Cell Physiol. 274: C1429–C1452
Déry O, Thoma MS, Wong H, Grady EF, Bunnett NW . 1999 J. Biol. Chem. 274: 18524–18535
Faruqi TR, Weiss EJ, Shapiro MJ, Huang W, Coughlin SR . 2000 J. Biol. Chem. 275: 19728–19734
Franke RR, Konig B, Sakmar TP, Khorana HG, Hofmann KP . 1990 Science 250: 123–125
Gerszten RE, Chen J, Ishii M, Ishii K, Wang L, Nanevicz T, Turck CW, Vu T-KH, Coughlin SR . 1994 Nature 368: 648–651
Grand RJA, Turnell AS, Grabham PW . 1996 Biochem. J. 313: 353–368
Hammes SR, Coughlin SR . 1999 Biochemistry 38: 2486–2493
Hammes SR, Shapiro MJ, Coughlin SR . 1999 Biochemistry 38: 9308–9316
Hein L, Ishii K, Coughlin SR, Kobilka BK . 1994 J. Biol. Chem. 269: 27719–27726
Hoekstra WJ, Hulshizer BL, McComsey DF, Andrade-Gordon P, Kauffman JA, Addo MF, Oksenberg D, Scarborough RM, Maryanoff BE . 1998 Bioorg. Med. Chem. Lett. 8: 1649–1654
Hollenberg MD, Yang S-G, Laniyonu AA, Moore GJ, Saifeddine M . 1992 Mol. Pharmacol. 42: 186–191
Hollenberg MD, Saifeddine M, Al-Ani B, Kawabata A . 1997 Can. J. Physiol. Pharmacol. 75: 832–841
Hollenberg MD . 1999 Trends Pharmacol. Sci. 20: 271–273
Hollenberg MD, Saifeddine M, Al-Ani B, Gui Y . 1999 Can. J. Physiol. Pharmacol. 77: 458–464
Horvat R, Palade GE . 1995 J. Cell Sci. 108: 1155–1164
Hoxie JA, Ahuja M, Belmonte E, Pizarro S, Parton RG, Brass LF . 1993 J. Biol. Chem. 268: 13756–13763
Hung DT, Thien-Khai HV, Nelken NA, Coughlin SR . 1992a J. Cell Biol. 116: 827–832
Hung DT, Vu T-KH, Wheaton VI, Charo IF, Nelken NA, Esmon N, Esmon CT, Coughlin SR . 1992b J. Clin. Invest. 89: 444–450
Hung DT, Wong YH, Vu T-KH, Coughlin SR . 1992c J. Biol. Chem. 267: 20831–20834
Iaccarino G, Rockman HA, Shotwell KF, Tomhave ED, Koch WJ . 1998 Am. J. Physiol. Heart Circ. Physiol. 44: H1298–H1306
Ido M, Hayashi T, Gabazza EC, Suzuki K . 2000 Thromb. Haemost. 83: 617–621
Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW, Timmons C, Tram T, Coughlin SR . 1997 Nature 386: 502–508
Ishii K, Hein L, Kobilka B, Coughlin SR . 1993 J. Biol. Chem. 268: 9780–9786
Ishii K, Chen J, Ishii M, Koch WJ, Freedman NJ, Lefkowitz RJ, Coughlin SR . 1994 J. Biol. Chem. 269: 1125–1130
Jenkins AL, Chinni C, De Niese MR, Blackhart B, Mackie EJ . 2000 Dev. Dyn. 218: 465–471
Jia M, Li MX, Dunlap V, Nelson PG . 1999 J. Neurobiol. 38: 369–381
Kahn ML, Hammes SR, Botka C, Coughlin SR . 1998a J. Biol. Chem. 273: 23290–23296
Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng DW, Moff S, Farese Jr. RV, Tam C, Coughlin SR . 1998b Nature 394: 690–694
Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR . 1999 J. Clin. Invest. 103: 879–887
Kawabata A, Saifeddine M, Al-Ani B, Leblond L, Hollenberg MD . 1999 J. Pharmacol. Exp. Ther. 288: 358–370
LaRosa CA, Rohrer MJ, Benoit SE, Rodino LJ, Barnard MR, Michelson AD . 1994 J. Vasc. Surg. 19: 306–319
Lerner DJ, Chen M, Tram T, Coughlin SR . 1996 J. Biol. Chem. 271: 13943–13947
LeRoy EC, Ager A, Gordon JL . 1984 J. Clin. Invest. 74: 1003–1010
Martin BM, Feinman RD, Detwiler TC . 1975 Biochemistry 14: 1308–1314
Martin BM, Wasiewski WW, Fenton JW, Detwiler TC . 1976 Biochemistry 15: 4886–4893
McComsey DF, Hecker LR, Andrade-Gordon P, Addo MF, Maryanoff BE . 1999 Bioorg. Med. Chem. Lett. 9: 255–260
Mirza H, Yatsula V, Bahou WF . 1996 J. Clin. Invest. 97: 1705–1714
Molino M, Di Lallo M, De Gaetano G, Cerletti C . 1992 Biochem. J. 288: 741–745
Molino M, Blanchard N, Belmonte E, Tarver AP, Abrams C, Hoxie JA, Cerletti C, Brass LF . 1995 J. Biol. Chem. 270: 11168–11175
Molino M, Bainton DF, Hoxie JA, Coughlin SR, Brass LF . 1997a J. Biol. Chem. 272: 6011–6017
Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A, Hoxie J, Schechter N, Woolkalis MI, Brass LF . 1997b J. Biol. Chem. 272: 4043–4049
Molino M, Woolkalis MJ, Reavey-Cantwell J, Pratico D, Andrade-Gordon P, Barnathan ES, Brass LF . 1997c J. Biol. Chem. 272: 11133–11141
Nakanishi-Matsui M, Zheng YW, Sulciner DJ, Weiss EJ, Ludeman MJ, Coughlin SR . 2000 Nature 404: 609–610
Nanevicz T, Ishii M, Wang L, Chen M, Chen J, Turck CW, Cohen FE, Coughlin SR . 1995 J. Biol. Chem. 270: 21619–21625
Nanevicz T, Wang L, Chen M, Ishii M, Coughlin SR . 1996 J. Biol. Chem. 271: 702–706
Natarajan S, Riexinger D, Peluso M, Seiler SM . 1995 Int. J. Pept. Protein Res. 45: 145–151
Nelken NA, Soifer SJ, O'Keefe J, Vu T-KH, Charo IF, Coughlin SR . 1992 J. Clin. Invest. 90: 1614–1621
Ngaiza JR, Manley G, Grulich-Henn J, Krstenansky JL, Jaffe EA . 1992 J. Cell. Physiol. 151: 190–196
Nystedt S, Emilsson K, Wahlestedt C, Sundelin J . 1994 Proc. Natl. Acad. Sci. USA 91: 9208–9212
Nystedt S, Emilsson K, Larsson AK, Strömbeck B, Sundelin J . 1995a Eur. J. Biochem. 232: 84–89
Nystedt S, Larsson A-K, Aberg H, Sundelin J . 1995b J. Biol. Chem. 270: 5950–5955
Nystedt S, Ramakrishnan V, Sundelin J . 1996 J. Biol. Chem. 271: 14910–14915
O'Brien PJ, Prevost N, Molino M, Hollinger MK, Woolkalis MJ, Woulfe DS, Brass LF . 2000 J. Biol. Chem. 275: 13502–13509
Okamoto T, Schlegel A, Scherer PE, Lisanti MP . 1998 J. Biol. Chem. 273: 5419–5422
Paris S, Pouysségur J . 1986 EMBO J. 5: 55–60
Parry MAA, Myles T, Tschopp J, Stone SR . 1996 Biochem. J. 320: 335–341
Petersen LC, Thastrup O, Hagel G, Sorensen BB, Freskgård PO, Rao LVM, Ezban M . 2000 Thromb. Haemost. 83: 571–576
Rasmussen UB, Vouret-Craviari V, Jallat S, Schlesinger Y, Pagès G, Pavirani A, Lecocq J-P, Pouysségur J, Van Obberghen-Schilling E . 1991 FEBS Lett. 288: 123–128
Renesto P, Si-Tahar M, Moniatte M, Balloy V, Van Dorsselaer A, Pidard D, Chignard M . 1997 Blood 89: 1944–1953
Riewald M, Kravenchko V, Petrovan RJ, Brass LF, Ulevitch R, Ruf W . 2000 Blood Suppl. 1, abstract
Rittenhouse-Simmons S . 1979 J. Clin. Invest. 63: 580–587
Salahpour A, Angers S, Bouvier M . 2000 Trends Endocrinol. Metab. 11: 163–168
Sambrano GR, Huang W, Faruqi T, Mahrus S, Craik C, Coughlin SR . 2000 J. Biol. Chem. 275: 6819–6823
Scarborough RM, Naughton MA, Teng W, Hung DT, Rose J, Vu T-KH, Wheaton VI, Turck CW, Coughlin SR . 1992 J. Biol. Chem. 267: 13146–13149
Schecter NM, Brass LF, Lavker RM, Jensen PJ . 1998 J. Cell. Physiol. 176: 365–373
Schmidt VA, Nierman WC, Maglott DR, Cupit LD, Moskowitz KA, Wainer JA, Bahou WF . 1998 J. Biol. Chem. 273: 15061–15068
Seiler SM, Peluso M, Michel IM, Goldenberg H, Fenton JW, II, Riexinger D, Natarajan S . 1995 Biochem. Pharmacol. 49: 519–528
Selak MA, Chignard M, Smith JB . 1988 Biochem. J. 251: 293–299
Shapiro MJ, Trejo J, Zeng D, Coughlin SR . 1996 J. Biol. Chem. 271: 32874–32880
Shapiro MJ, Weiss EJ, Faruqi TR, Coughlin SR . 2000 J. Biol. Chem. 275: 25216–25221
Shuman MA . 1986 Ann. NY. Acad. Sci. 485: 228–239
Sorensen BB, Freskgård PO, Soegaard N, Rao LVM, Ezban M, Petersen LC . 1999 J. Biol. Chem. 274: 21349–21354
Suidan HS, Bouvier J, Schaerer E, Stone SR, Monard D, Tschopp J . 1994 Proc. Natl. Acad. Sci. USA 91: 8112–8116
Suidan HS, Clemetson KJ, Brown-Luedi M, Niclou SP, Clemetson JM, Tschopp J, Monard D . 1996 Biochem. J. 315: 939–945
Takeuchi T, Harris JL, Huang W, Yan KW, Coughlin SR, Craik CS . 2000 J. Biol. Chem. 275: 26333–26342
Tiruppathi C, Yan WH, Sandoval R, Naqvi T, Pronin AN, Benovic JL, Malik AB . 2000 Proc. Natl. Acad. Sci. USA 97: 7440–7445
Totani L, Piccoli A, Pellegrini G, Di Santo A, Lorenzet R . 1994 Arterioscler. Thromb. 14: 125–132
Trejo J, Hammes SR, Coughlin SR . 1998 Proc. Natl. Acad. Sci. USA 95: 13698–13702
Trejo J, Coughlin SR . 1999 J. Biol. Chem. 274: 2216–2224
Vassallo Jr RR, Kieber-Emmons T, Cichowski K, Brass LF . 1992 J. Biol. Chem. 267: 6081–6085
Vouret-Craviari V, Auberger P, Pouysségur J, Van Obberghen-Schilling E . 1995a J. Biol. Chem. 270: 4813–4821
Vouret-Craviari V, Grall D, Chambard J-C, Rasmussen UB, Pouysségur J, Van Obberghen-Schilling E . 1995b J. Biol. Chem. 270: 8367–8372
Vu T-KH, Hung DT, Wheaton VI, Coughlin SR . 1991a Cell 64: 1057–1068
Vu T-KH, Wheaton VI, Hung DT, Charo I, Coughlin SR . 1991b Nature 353: 674–677
Weksler BB, Jaffe EA, Brower MS, Cole OF . 1989 Blood 74: 1627–1634
Woolkalis MJ, DeMelfi TM, Blanchard N, Hoxie JA, Brass LF . 1995a Thromb. Haemost. 73: 929
Woolkalis MJ, DeMelfi TM, Blanchard N, Hoxie JA, Brass LF . 1995b J. Biol. Chem. 270: 9868–9875
Xu W-F, Andersen H, Whitmore TE, Presnell Sr, Yee DP, Ching AC, Gilbert T, Davie EW, Foster DC . 1998 Proc. Natl. Acad. Sci. USA 95: 6642–6646
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This work was supported by the NIH HLBI (HL40387).
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O'Brien, P., Molino, M., Kahn, M. et al. Protease activated receptors: theme and variations. Oncogene 20, 1570–1581 (2001). https://doi.org/10.1038/sj.onc.1204194
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