Abstract
The members of the convertase family play a central role in the processing of various protein precursors ranging from hormones and growth factors to viral envelope proteins and bacterial toxins. The proteolysis of these precursors that occurs at basic residues is mediated by the proprotein convertases (PCs), namely: PC1, PC2, Furin, PACE4, PC4, PC5 and PC7. The proteolysis at non-basic residues is performed by subtilisin/kexin-like isozyme-1 (S1P/SKI-1) and the newly identified neural apoptosis-regulated convertase-1 (NARC-1/PCSK9). These proteases have key roles in many physiological processes and various pathologies including cancer, obesity, diabetes, neurodegenerative diseases and autosomal dominant hypercholesterolermia. Here we summarize the discovery of the proprotein convertases and their inhibitors, discuss their properties, roles, resemblance and differences
Keywords: Proprotein convertases, SKI-1/S1P, NARC-1/PCSK9, Prosegments, α1-PDX, 7B2, ProSAAS
References
- [1].Khatib AM, Siegfried G, Chretien M, Metrakos P, Seidah NG. Proprotein convertases in tumor progression and malignancy: Novel targets in cancer therapy. Am J Pathol. 2002;160:1921–1935. doi: 10.1016/S0002-9440(10)61140-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Nakayama K. Furin: A mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J. 1997;327:625–635. doi: 10.1042/bj3270625. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Zhou A, Webb G, Zhu X, Steiner DF. Proteolytic processing in the secretory pathway. J Biol Chem. 1999;274:20745–20748. doi: 10.1074/jbc.274.30.20745. [DOI] [PubMed] [Google Scholar]
- [4].Seidah NG, Chretien M, Day R. The family of subtilisin/kexin like pro-protein and pro-hormone convertases: Divergent or shared functions. Biochimie. 1994;76:197–209. doi: 10.1016/0300-9084(94)90147-3. [DOI] [PubMed] [Google Scholar]
- [5].Julius D, Brake A, Blair L, Kunisawa R, Thorner J. Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-alpha-factor. Cell. 1984;37:1075–1089. doi: 10.1016/0092-8674(84)90442-2. [DOI] [PubMed] [Google Scholar]
- [6].Mizuno K, Nakamura T, Ohshima T, Tanaka S, Matsuo H. Yeast KEX2 genes encodes an endopeptidase homologous to subtilisin-like serine proteases. Biochem Biophys Res Commun. 1988;156:246–254. doi: 10.1016/S0006-291X(88)80832-5. [DOI] [PubMed] [Google Scholar]
- [7].Fuller RS, Brake AJ, Thorner J. Intracellular targeting and structural conservation of a prohormone-processing endoprotease. Science. 1989;246:482–486. doi: 10.1126/science.2683070. [DOI] [PubMed] [Google Scholar]
- [8].Roebroek AJ, Schalken JA, Bussemakers MJ, van Heerikhuizen H, Onnekink C, Debruyne FM, Bloemers HP, Van de Ven WJ. Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene. Mol Biol Rep. 1986;11:117–125. doi: 10.1007/BF00364823. [DOI] [PubMed] [Google Scholar]
- [9].Roebroek AJ, Schalken JA, Leunissen JA, Onnekink C, Bloemers HP, Van de Ven WJ. Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein. EMBO J. 1986;59:2197–2202. doi: 10.1002/j.1460-2075.1986.tb04484.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].van de Ven WJ, Voorberg J, Fontijn R, Pannekoek H, van den Ouweland AM, van Duijnhoven HL, Roebroek AJ, Siezen RJ. Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Mol Biol Rep. 1990;14:265–275. doi: 10.1007/BF00429896. [DOI] [PubMed] [Google Scholar]
- [11].Leduc R, Molloy SS, Thorne BA, Thomas G. Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage. J Biol Chem. 1992;267:14304–14308. [PubMed] [Google Scholar]
- [12].Creemers JW, Siezen RJ, Roebroek AJ, Ayoubi TA, Huylebroeck D, Van de Ven WJ. Modulation of furin-mediated proprotein processing activity by site-directed mutagenesis. J Biol Chem. 1993;268:21826–21834. [PubMed] [Google Scholar]
- [13].Takahashi S, Nakagawa T, Kasai K, Banno T, Duguay SJ, Van de Ven WJ, Murakami K, Nakayama K. A second mutant allele of furin in the processing-incompetent cell line, LoVo. Evidence for involvement of the homo B domain in autocatalytic activation. J Biol Chem. 1995;270:26565–26569. doi: 10.1074/jbc.270.44.26565. [DOI] [PubMed] [Google Scholar]
- [14].Molloy SS, Thomas L, VanSlyke JK, Stenberg PE, Thomas G. Intracellular trafficking and activation of the furin proprotein convertase: Localization to the TGN and recycling from the cell surface. EMBO J. 1994;13:18–33. doi: 10.1002/j.1460-2075.1994.tb06231.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Seidah NG, Gaspar L, Mion P, Marcinkiewicz M, Mbikay M, Chretien M. cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: Tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases. DNA Cell Biol. 1990;9:415–424. doi: 10.1089/dna.1990.9.415. [DOI] [PubMed] [Google Scholar]
- [16].Smeekens SP, Steiner DF. Identification of a human insulinoma cDNA encoding a novel mammalian protein structurally related to the yeast dibasic processing protease Kex2. J Biol Chem. 1990;265:2997–3000. [PubMed] [Google Scholar]
- [17].Smeekens SP, Avruch AS, LaMendola J, Chan SJ, Steiner DF. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proc Natl Acad Sci U S A. 1991;88:340–344. doi: 10.1073/pnas.88.2.340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Seidah NG, Marcinkiewicz M, Benjannet S, Gaspar L, Beaubien G, Mattei MG, Lazure C, Mbikay M, Chretien M. Cloning and primary sequence of a mouse candidate prohormone convertase PC1 homologous to PC2, Furin, and Kex2: Distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Mol Endocrinol. 1991;5:111–122. doi: 10.1210/mend-5-1-111. [DOI] [PubMed] [Google Scholar]
- [19].Korner J, Chun J, Harter D, Axel R. Isolation and functional expression of a mammalian prohormone processing enzyme, murine prohormone convertase 1. Proc Natl Acad Sci U S A. 1991;88:6834–6838. doi: 10.1073/pnas.88.15.6834. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Steiner DF, Smeekens SP, Ohagi S, Chan SJ. The new enzymology of precursor processing endoproteases. J Biol Chem. 1992;267:23435–23438. [PubMed] [Google Scholar]
- [21].Seidah NG, Benjannet S, Hamelin J, Mamarbachi AM, Basak A, Marcinkiewicz J, Mbikay M, Chretien M, Marcinkiewicz M. The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Ann N Y Acad Sci. 1999;885:57–74. doi: 10.1111/j.1749-6632.1999.tb08665.x. [DOI] [PubMed] [Google Scholar]
- [22].Bell ME, Myers TR, Myers DA. Expression of proopiomelanocortin and prohormone convertase-1 and -2 in the late gestation fetal sheep pituitary. Endocrinology. 1998;139:5135–5143. doi: 10.1210/en.139.12.5135. [DOI] [PubMed] [Google Scholar]
- [23].Steiner DF, Rouille Y, Gong Q, Martin S, Carroll R, Chan SJ. The role of prohormone convertases in insulin biosynthesis: Evidence for inherited defects in their action in man and experimental animals. Diabetes Metab. 1996;22:94–104. [PubMed] [Google Scholar]
- [24].Mineo I, Matsumura T, Shingu R, Namba M, Kuwajima M, Matsuzawa Y. The role of prohormone convertases PC1 (PC3) and PC2 in the cell-specific processing of proglucagon. Biochem Biophys Res Commun. 1995;207:646–651. doi: 10.1006/bbrc.1995.1236. [DOI] [PubMed] [Google Scholar]
- [25].Vindrola O, Lindberg I. Biosynthesis of the prohormone convertase mPC1 in AtT-20 cells. Mol Endocrinol. 1992;6:1088–1094. doi: 10.1210/me.6.7.1088. [DOI] [PubMed] [Google Scholar]
- [26].Shennan KI, Taylor NA, Jermany JL, Matthews G, Docherty K. Differences in pH optima and calcium requirements for maturation of the prohormone convertases PC2 and PC3 indicates different intracellular locations for these events. J Biol Chem. 1995;270:1402–1407. doi: 10.1074/jbc.270.3.1402. [DOI] [PubMed] [Google Scholar]
- [27].Crine P, Gossard F, Seidah N, Blanchette L, Lis M, Chretien M. Concomitant synthesis of beta-endorphin and alpha-melanotropin from two forms of pro-opiomelanocortin in the rat pars intermedia. Proc Natl Acad Sci U S A. 1979;76:5085–5089. doi: 10.1073/pnas.76.10.5085. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Benjannet S, Rondeau N, Day R, Chretien M, Seidah NG. PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proc Natl Acad Sci U S A. 1991;88:3564–3568. doi: 10.1073/pnas.88.9.3564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [29].Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ. Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15. DNA Cell Biol. 1991;10:757–769. doi: 10.1089/dna.1991.10.757. [DOI] [PubMed] [Google Scholar]
- [30].Laprise MH, Grondin F, Cayer P, McDonald PP, Dubois CM. Furin gene (fur) regulation in differentiating human megakaryoblastic Dami cells: Involvement of the proximal GATA recognition motif in the P1 promoter and impact on the maturation of furin substrates. Blood. 2002;100:3578–3587. doi: 10.1182/blood.V100.10.3578. [DOI] [PubMed] [Google Scholar]
- [31].Nagahama M, Taniguchi T, Hashimoto E, Imamaki A, Mori K, Tsuji A, Matsuda Y. Biosynthetic processing and quaternary interactions of proprotein convertase SPC4 (PACE4) FEBS Lett. 1998;434:155–159. doi: 10.1016/S0014-5793(98)00970-3. [DOI] [PubMed] [Google Scholar]
- [32].Taniguchi T, Kuroda R, Sakurai K, Nagahama M, Wada I, Tsuji A, Matsuda Y. A critical role for the carboxy terminal region of the proprotein convertase, PACE4A, in the regulation of its autocatalytic activation coupled with secretion. Biochem Biophys Res Commun. 2002;290:878–884. doi: 10.1006/bbrc.2001.6282. [DOI] [PubMed] [Google Scholar]
- [33].Tsuji A, Sakurai K, Kiyokage E, Yamazaki T, Koide S, Toida K, Ishimura K, Matsuda Y. Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix. Potential role of PACE4 in the activation of proproteins in the extracellular matrix. Biochim Biophys Acta. 2003;1645:95–104. doi: 10.1016/s1570-9639(02)00532-0. [DOI] [PubMed] [Google Scholar]
- [34].Nour N, Mayer G, Mort JS, Salvas A, Mbikay M, Morrison CJ, Overall CM, Seidah NG. The cysteine-rich domain of the secreted proprotein convertases PC5A and PACE4 functions as a cell surface anchor and interacts with tissue inhibitors of metalloproteinases. Mol Biol Cell. 2005;16:5215–5226. doi: 10.1091/mbc.E05-06-0504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [35].Bando M, Matsuoka A, Tsuji A, Matsuda Y. The proprotein convertase PACE4 is upregulated by PDGF-BB in megakaryocytes: Gene expression of PACE4 and furin is regulated differently in Dami cells. J Biochem (Tokyo) 2002;132:127–134. doi: 10.1093/oxfordjournals.jbchem.a003189. [DOI] [PubMed] [Google Scholar]
- [36].Blanchette F, Day R, Dong W, Laprise MH, Dubois CM. TGFbeta1 regulates gene expression of its own converting enzyme furin. J Clin Invest. 1997;99:1974–1983. doi: 10.1172/JCI119365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [37].Yoshida I, Koide S, Hasegawa SI, Nakagawara A, Tsuji A, Matsuda Y. Proprotein convertase PACE4 is down-regulated by the basic helix-loop-helix transcription factor hASH-1 and MASH-1. Biochem J. 2001;360:683–689. doi: 10.1042/0264-6021:3600683. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [38].Nakayama K, Kim WS, Torii S, Hosaka M, Nakagawa T, Ikemizu J, Baba T, Murakami K. Identification of the fourth member of the mammalian endoprotease family homologous to the yeast Kex2 protease. Its testis-specific expression. J Biol Chem. 1992;267:5897–5900. [PubMed] [Google Scholar]
- [39].Seidah NG, Day R, Hamelin J, Gaspar A, Collard MW, Chretien M. Testicular expression of PC4 in the rat: Molecular diversity of a novel germ cell-specific Kex2/subtilisin-like proprotein convertase. Mol Endocrinol. 1992;6:1559–1570. doi: 10.1210/me.6.10.1559. [DOI] [PubMed] [Google Scholar]
- [40].Torii S, Yamagishi T, Murakami K, Nakayama K. Localization of Kex2-like processing endoproteases, furin and PC4, within mouse testis by in situ hybridization. FEBS Lett. 1993;316:12–16. doi: 10.1016/0014-5793(93)81726-G. [DOI] [PubMed] [Google Scholar]
- [41].Li M, Mbikay M, Nakayama K, Miyata A, Arimura A. Prohormone convertase PC4 processes the precursor of PACAP in the testis. Ann N Y Acad Sci. 2000;921:333–339. doi: 10.1111/j.1749-6632.2000.tb06988.x. [DOI] [PubMed] [Google Scholar]
- [42].Lusson J, Vieau D, Hamelin J, Day R, Chretien M, Seidah NG. cDNA structure of the mouse and rat subtilisin/kexin-like PC5: A candidate proprotein convertase expressed in endocrine and nonendocrine cells. Proc Natl Acad Sci U S A. 1993;90:6691–6695. doi: 10.1073/pnas.90.14.6691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [43].Nakagawa T, Hosaka M, Torii S, Watanabe T, Murakami K, Nakayama K. Identification and functional expression of a new member of the mammalian Kex2-like processing endoprotease family: Its striking structural similarity to PACE4. J Biochem (Tokyo) 1993;113:132–135. doi: 10.1093/oxfordjournals.jbchem.a124015. [DOI] [PubMed] [Google Scholar]
- [44].Stawowy P, Blaschke F, Kilimnik A, Goetze S, Kallisch H, Chretien M, Marcinkiewicz M, Fleck E, Graf K. Proprotein convertase PC5 regulation by PDGF-BB involves PI3-kinase/p70(s6)-kinase activation in vascular smooth muscle cells. Hypertension. 2002;39:399–404. doi: 10.1161/hy0202.103000. [DOI] [PubMed] [Google Scholar]
- [45].Siegfried G, Khatib AM, Benjannet S, Chretien M, Seidah NG. The proteolytic processing of pro-platelet-derived growth factor-A at RRKR(86) by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity. Cancer Res. 2003;63:1458–1463. [PubMed] [Google Scholar]
- [46].Siegfried G, Basak A, Prichett-Pejic W, Scamuffa N, Ma L, Benjannet S, Veinot JP, Calvo F, Seidah N, Khatib AM. Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases. Oncogene. 2005;24:6925–6935. doi: 10.1038/sj.onc.1208838. [DOI] [PubMed] [Google Scholar]
- [47].Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chretien M, Seidah NG, Khatib AM. The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest. 2003;111:1723–1732. doi: 10.1172/JCI200317220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [48].Lissitzky JC, Luis J, Munzer JS, Benjannet S, Parat F, Chretien M, Marvaldi J, Seidah NG. Endoproteolytic processing of integrin pro-alpha subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7. Biochem J. 2000;346:133–138. doi: 10.1042/0264-6021:3460133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [49].Kalus I, Schnegelsberg B, Seidah NG, Kleene R, Schachner M. The proprotein convertase PC5A and a metalloprotease are involved in the proteolytic processing of the neural adhesion molecule L1. J Biol Chem. 2003;278:10381–10388. doi: 10.1074/jbc.M208351200. [DOI] [PubMed] [Google Scholar]
- [50].Ulloa L, Creemers JW, Roy S, Liu S, Mason J, Tabibzadeh S. Lefty proteins exhibit unique processing and activate the MAPK pathway. J Biol Chem. 2001;276:21387–21396. doi: 10.1074/jbc.M006933200. [DOI] [PubMed] [Google Scholar]
- [51].Nour N, Basak A, Chretien M, Seidah NG. Structure-function analysis of the prosegment of the proprotein convertase PC5A. J Biol Chem. 2003;278:2886–2895. doi: 10.1074/jbc.M208009200. [DOI] [PubMed] [Google Scholar]
- [52].Seidah NG, Hamelin J, Mamarbachi M, Dong W, Tardos H, Mbikay M, Chretien M, Day R. cDNA structure, tissue distribution, and chromosomal localization of rat PC7, a novel mammalian proprotein convertase closest to yeast kexin-like proteinases. Proc Natl Acad Sci U S A. 1996;93:3388–3393. doi: 10.1073/pnas.93.8.3388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [53].Bruzzaniti A, Goodge K, Jay P, Taviaux SA, Lam MH, Berta P, Martin TJ, Moseley JM, Gillespie MT. PC8 [corrected], a new member of the convertase family. Biochem J. 1996;314:727–731. doi: 10.1042/bj3140727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [54].Meerabux J, Yaspo ML, Roebroek AJ, Van de Ven WJ, Lister TA, Young BD. A new member of the proprotein convertase gene family (LPC) is located at a chromosome translocation breakpoint in lymphomas. Cancer Res. 1996;56:448–451. [PubMed] [Google Scholar]
- [55].Taylor NA, Van De Ven WJ, Creemers JW. Curbing activation: Proprotein convertases in homeostasis and pathology. FASEB J. 2003;17:1215–1227. doi: 10.1096/fj.02-0831rev. [DOI] [PubMed] [Google Scholar]
- [56].Constam DB, Robertson EJ. Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J Cell Biol. 1999;144:139–149. doi: 10.1083/jcb.144.1.139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [57].Constam DB, Calfon M, Robertson EJ. SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis. J Cell Biol. 1996;134:181–191. doi: 10.1083/jcb.134.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [58].Seidah NG, Mowla SJ, Hamelin J, Mamarbachi AM, Benjannet S, Toure BB, Basak A, Munzer JS, Marcinkiewicz J, Zhong M, Barale JC, Lazure C, Murphy RA, Chretien M, Marcinkiewicz M. Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization. Proc Natl Acad Sci U S A. 1999;96:1321–1326. doi: 10.1073/pnas.96.4.1321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [59].Sakai J, Rawson RB, Espenshade PJ, Cheng D, Seegmiller AC, Goldstein JL, Brown MS. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell. 1998;2:505–514. doi: 10.1016/S1097-2765(00)80150-1. [DOI] [PubMed] [Google Scholar]
- [60].Brown MS, Goldstein JL. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89:331–340. doi: 10.1016/S0092-8674(00)80213-5. [DOI] [PubMed] [Google Scholar]
- [61].Lenz O, ter Meulen J, Klenk HD, Seidah NG, Garten W. The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P. Proc Natl Acad Sci U S A. 2001;98:12701–12705. doi: 10.1073/pnas.221447598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [62].Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000;6:1355–1364. doi: 10.1016/S1097-2765(00)00133-7. [DOI] [PubMed] [Google Scholar]
- [63].Yang J, Goldstein JL, Hammer RE, Moon YA, Brown MS, Horton JD. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc Natl Acad Sci U S A. 2001;98:13607–13612. doi: 10.1073/pnas.201524598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [64].Mouchantaf R, Watt HL, Sulea T, Seidah NG, Alturaihi H, Patel YC, Kumar U. Prosomatostatin is proteolytically processed at the amino terminal segment by subtilase SKI-1. Regul Pept. 2004;120:133–140. doi: 10.1016/j.regpep.2004.02.022. [DOI] [PubMed] [Google Scholar]
- [65].Stirling J, O’hare P. CREB4, a Transmembrane bZip Transcription Factor and Potential New Substrate for Regulation and Cleavage by S1P. Mol Biol Cell. 2006;17:413–426. doi: 10.1091/mbc.E05-06-0500. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [66].Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100:928–933. doi: 10.1073/pnas.0335507100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [67].Naureckiene S, Ma L, Sreekumar K, Purandare U, Frederick Lo C, Huang Y, Chiang LW, Grenier JM, Ozenberger BA, Steven Jacobsen J, Kennedy JD, DiStefano PS, Wood A, Bingham B. Functional characterization of Narc 1, a novel proteinase related to proteinase K. Arch Biochem Biophys. 2003;420:55–67. doi: 10.1016/j.abb.2003.09.011. [DOI] [PubMed] [Google Scholar]
- [68].Seidah NG. Cellular limited proteolysis of precursor proteins and peptides. In: Dalbey RE, Sigman DS, editors. The Enzymes: Co- and Posttranslational Proteolysis of Proteins. San Diego, CA: Academic Press; 2001. pp. 237–258. [Google Scholar]
- [69].Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–156. doi: 10.1038/ng1161. [DOI] [PubMed] [Google Scholar]
- [70].Attie AD, Seidah NG. Dual regulation of the LDL receptor – some clarity and new questions. Cell Metab. 2005;1:290–292. doi: 10.1016/j.cmet.2005.04.006. [DOI] [PubMed] [Google Scholar]
- [71].Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–165. doi: 10.1038/ng1509. [DOI] [PubMed] [Google Scholar]
- [72].Jutras I, Seidah NG, Reudelhuber TL, Brechler V. Two activation states of the prohormone convertase PC1 in the secretory pathway. J Biol Chem. 1997;272:15184–15188. doi: 10.1074/jbc.272.24.15184. [DOI] [PubMed] [Google Scholar]
- [73].Fricker LD, McKinzie AA, Sun J, Curran E, Qian Y, Yan L, Patterson SD, Courchesne PL, Richards B, Levin N, Mzhavia N, Devi LADouglass J. Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing. J. Neurosci. 2000;20:639–648. doi: 10.1523/JNEUROSCI.20-02-00639.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [74].Basak A, Koch P, Dupelle M, Fricker LD, Devi LA, Chretien MSeidah NG. Inhibitory specificity and potency of proSAAS-derived peptides toward proprotein convertase 1. J. Biol. Chem. 2001;276:32720–32728. doi: 10.1074/jbc.M104064200. [DOI] [PubMed] [Google Scholar]
- [75].Mbikay M, Seidah NGChretien M. Neuroendocrine secretory protein 7B2: Structure, expression and functions. Biochem. J. 2001;357:329–342. doi: 10.1042/0264-6021:3570329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [76].Hsi KL, Seidah NG, De Serres G, Chretien M. Isolation and NH2-terminal sequence of a novel porcine anterior pituitary polypeptide. Homology to proinsulin, secretin and Rous sarcoma virus transforming protein TVFV60. FEBS Lett. 1982;147:261–266. doi: 10.1016/0014-5793(82)81055-7. [DOI] [PubMed] [Google Scholar]
- [77].Seidah NG, Hsi KL, De Serres G, Rochemont J, Hamelin J, Antakly T, Cantin M, Chretien M. Isolation and NH2-terminal sequence of a highly conserved human and porcine pituitary protein belonging to a new superfamily. Immunocytochemical localization in pars distalis and pars nervosa of the pituitary and in the supraoptic nucleus of the hypothalamus. Arch Biochem Biophys. 1983;225:525–534. doi: 10.1016/0003-9861(83)90063-2. [DOI] [PubMed] [Google Scholar]
- [78].Marcinkiewicz M, Benjannet S, Falgueyret JP, Seidah NG, Schurch W, Verdy M, Cantin M, Chretien M. Identification and localization of 7B2 protein in human, porcine, and rat thyroid gland and in human medullary carcinoma. Endocrinology. 1988;123:866–873. doi: 10.1210/endo-123-2-866. [DOI] [PubMed] [Google Scholar]
- [79].Fricker LD, McKinzie AA, Sun J, Curran E, Qian Y, Yan L, Patterson SD, Courchesne PL, Richards B, Levin N, Mzhavia N, Devi LA, Douglass J. Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing. J Neurosci. 2000;20:639–648. doi: 10.1523/JNEUROSCI.20-02-00639.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [80].Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat Genet. 1995;10:135–142. doi: 10.1038/ng0695-135. [DOI] [PubMed] [Google Scholar]
- [81].Qian Y, Devi LA, Mzhavia N, Munzer S, Seidah NG, Fricker LD. The C-terminal region of proSAAS is a potent inhibitor of prohormone convertase 1. J Biol Chem. 2000;275:23596–23601. doi: 10.1074/jbc.M001583200. [DOI] [PubMed] [Google Scholar]
- [82].Zhu X, Lindberg I. 7B2 facilitates the maturation of proPC2 in neuroendocrine cells and is required for the expression of enzymatic activity. J Cell Biol. 1995;129:1641–1650. doi: 10.1083/jcb.129.6.1641. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [83].Benjannet S, Rondeau N, Day R, Chretien M, Seidah N. PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proc. Natl. Acad. Sci. U. S. A. 1991;88:3564–3568. doi: 10.1073/pnas.88.9.3564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [84].Boudreault A, Gauthier D, Rondeau N, Savaria D, Seidah N, Chretien M, Lazure C. Molecular characterization, enzymatic analysis, and purification of murine proprotein convertase-1/3 (PC1/PC3) secreted from recombinant baculovirus-infected insect cells. Prot. Exp. Purif. 1998;14:353–366. doi: 10.1006/prep.1998.0964. [DOI] [PubMed] [Google Scholar]
- [85].Wei S, Feng Y, Che FY, Pan H, Mzhavia N, Devi LA, McKinzie AA, Levin N, Richards WG, Fricker LD. Obesity and diabetes in transgenic mice expressing proSAAS. J Endocrinol. 2004;180:357–368. doi: 10.1677/joe.0.1800357. [DOI] [PubMed] [Google Scholar]
- [86].Anderson ED, VanSlyke JK, Thulin CD, Jean F, Thomas G. Activation of the furin endoprotease is a multiple-step process: Requirements for acidification and internal propeptide cleavage. EMBO J. 1997;16:1508–1518. doi: 10.1093/emboj/16.7.1508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [87].Zhong M, Munzer JS, Basak A, Benjannet S, Mowla SJ, Decroly E, Chrètien M, Seidah NG. The prosegments of furin and PC7 as potent inhibitors of proprotein convertases: In vitro and ex vivo assessment of their specificity and selectivity. J. Biol. Chem. 1999;274:33913–33920. doi: 10.1074/jbc.274.48.33913. [DOI] [PubMed] [Google Scholar]
- [88].Bhattacharjya S, Xu P, Zhong M, Chretien M, Seidah NG, Ni F. Inhibitory activity and structural characterization of a C-terminal peptide fragment derived from the prosegment of the proprotein convertase PC7. Biochemistry. 2000;39:2868–2877. doi: 10.1021/bi9923961. [DOI] [PubMed] [Google Scholar]
- [89].Boudreault A, Gauthier D, Lazure C. Proprotein convertase PC1/3-related peptides are potent slow tight-binding inhibitors of murine PC1/3 and Hfurin. J Biol Chem. 1998;273:31574–31580. doi: 10.1074/jbc.273.47.31574. [DOI] [PubMed] [Google Scholar]
- [90].Lazure C, Gauthier D, Jean F, Boudreault A, Seidah NG, Bennett HP, Hendy GN. In vitro cleavage of internally quenched fluorogenic human proparathyroid hormone and proparathyroid-related peptide substrates by furin. Generation of a potent inhibitor. J Biol Chem. 1998;273:8572–8580. doi: 10.1074/jbc.273.15.8572. [DOI] [PubMed] [Google Scholar]
- [91].Sawada Y, Inoue M, Kanda T, Sakamaki T, Tanaka S, Minamino N, Nagai R, Takeuchi T. Co-elevation of brain natriuretic peptide and proprotein-processing endoprotease furin after myocardial infarction in rats. FEBS Lett. 1997;400:177–182. doi: 10.1016/S0014-5793(96)01385-3. [DOI] [PubMed] [Google Scholar]
- [92].Lu W, Zhang W, Molloy SS, Thomas G, Ryan K, Chiang Y, Anderson S, Laskowski M., Jr Arg15-Lys17-Arg18 turkey ovomucoid third domain inhibits human furin. J Biol Chem. 1993;268:14583–14585. [PubMed] [Google Scholar]
- [93].Garten W, Hallenberger S, Ortmann D, Schafer W, Vey M, Angliker H, Shaw E, Klenk HD. Processing of viral glycoproteins by the subtilisin-like endoprotease furin and its inhibition by specific peptidylchloroalkylketones. Biochimie. 1994;76:217–225. doi: 10.1016/0300-9084(94)90149-X. [DOI] [PubMed] [Google Scholar]
- [94].Bathurst IC, Brennan SO, Carrell RW, Cousens LS, Brake AJ, Barr PJ. Yeast KEX2 protease has the properties of a human proalbumin converting enzyme. Science. 1987;235:348–350. doi: 10.1126/science.3541206. [DOI] [PubMed] [Google Scholar]
- [95].Brennan SO, Peach RJ. Calcium-dependent KEX2-like protease found in hepatic secretory vesicles converts proalbumin to albumin. FEBS Lett. 1988;229:167–170. doi: 10.1016/0014-5793(88)80819-6. [DOI] [PubMed] [Google Scholar]
- [96].Anderson ED, Thomas L, Hayflick JS, Thomas G. Inhibition of HIV-1 gp160-dependent membrane fusion by a furin-directed α 1-antitrypsin variant. J Biol Chem. 1993;268:24887–24891. [PubMed] [Google Scholar]
- [97].Jean F, Stella K, Thomas L, Liu G, Xiang Y, Reason AJ, Thomas G. α 1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: Application as an antipathogenic agent. Proc Natl Acad Sci USA. 1998;23:7293–7298. doi: 10.1073/pnas.95.13.7293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [98].Dufour EK, Denault JB, Hopkins PC, Leduc R. Serpin-like properties of alpha1-antitrypsin Portland towards furin convertase. FEBS Lett. 1998;426:41–46. doi: 10.1016/S0014-5793(98)00307-X. [DOI] [PubMed] [Google Scholar]
- [99].Vollenweider F, Benjannet S, Decroly E, Savaria D, Lazure C, Thomas G, Chrètien MSeidah NG. Comparative cellular processing of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp160 by the mammalian subtilisin/kexin-like convertases. Biochem J. 1996;314:521–532. doi: 10.1042/bj3140521. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [100].Benjannet S, Savaria D, Laslop A, Munzer JS, Chretien M, Marcinkiewicz M, Seidah NG (1997) Alpha1-antitrypsin Portland inhibits processing of precursors mediated by proprotein convertases primarily within the constitutive secretory pathway 272:26210–26218 [DOI] [PubMed]
- [101].Munzer JS, Basak A, Zhong M, Mamarbachi M, Hamelin J, Savaria D, Lazure C, Benjannet S, Chrètien MSeidah NG. In Vitro characterization of the novel proprotein convertase PC7. J Biol Chem. 1997;272:19672–19681. doi: 10.1074/jbc.272.32.19672. [DOI] [PubMed] [Google Scholar]
- [102].Lopez-Perez E, Seidah NG, Checler F. Proprotein convertase activity contributes to the processing of the Alzheimer’s β-amyloid precursor protein in human cells: Evidence for a role of the prohormone convertase PC7 in the constitutive α-secretase pathway. J Neurochem. 1999;73:2056–2062. [PubMed] [Google Scholar]
- [103].Abrami L, Fivaz M, Decroly E, Seidah NG, Jean F, Thomas G, Leppla SH, Buckley JT, van der Goot FG. The pore-forming toxin proaerolysin is activated by furin. J Biol Chem. 1998;273:32656–32661. doi: 10.1074/jbc.273.49.32656. [DOI] [PubMed] [Google Scholar]
- [104].Cui Y, Jean F, Thomas G, Christian JL. BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development. EMBO J. 1998;17:4735–4743. doi: 10.1093/emboj/17.16.4735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [105].Khatib AM, Siegfried G, Prat A, Luis J, Chretien M, Metrakos P, Seidah NG. Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells: Importance of insulin-like growth factor-1 (IGF-1) receptor processing in IGF-1-mediated functions. J Biol Chem. 2001;276:30686–30693. doi: 10.1074/jbc.M101725200. [DOI] [PubMed] [Google Scholar]
- [106].Van Rompaey L, Ayoubi T, Van De Ven W, Marynen P. Inhibition of intracellular proteolytic processing of soluble proproteins by an engineered alpha 2-macroglobulin containing a furin recognition sequence in the bait region. Biochem J. 1997;326:507–514. doi: 10.1042/bj3260507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [107].Dahlen JR, Jean F, Thomas G, Foster C, Kisiel W. Inhibition of Soluble Recombinant Furin by Human Proteinase Inhibitor 8. J Biol Chem. 1998;273:1851–1854. doi: 10.1074/jbc.273.4.1851. [DOI] [PubMed] [Google Scholar]
- [108].Cameron A, Appel J, Houghten RA, Lindberg I. Polyarginines Are Potent Furin Inhibitors. J Biol Chem. 2000;275:36741–36749. doi: 10.1074/jbc.M003848200. [DOI] [PubMed] [Google Scholar]
- [109].Roebroek AJ, Umans L, Pauli IG, Robertson EJ, van Leuven F, Van de Ven WJ, Constam DB. Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase furin. Development. 1998;125:4863–4876. doi: 10.1242/dev.125.24.4863. [DOI] [PubMed] [Google Scholar]
- [110].Essalmani R, Hamelin J, Marcinkiewwicz E, Chamberland A, Mbikay M, Chretien C, Seidah N.G, Prat A. Genetic deletion of PC/6 leads to early embryonic lethalithy. Mol.Cell Biol. 2006;26:354–361. doi: 10.1128/MCB.26.1.354-361.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [111].Yang J, Goldstein JL, Hammer RE, Moon YA, Brown MS, Horton JD. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc Natl Acad Sci U S A. 2001;98:13607–13612. doi: 10.1073/pnas.201524598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [112].Furuta M, Yano H, Zhou A, Rouille Y, Holst JJ, Carroll R, Ravazzola M, Orci L, Furuta H, Steiner DF. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc Natl Acad Sci U S A. 1997;94:6646–6651. doi: 10.1073/pnas.94.13.6646. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [113].Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst JJ, Steiner DF. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci U S A. 2002;99:10293–10298. doi: 10.1073/pnas.162352599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [114].Constam DB, Robertson EJ. SPC4/PACE4 regulates a TGFbeta signaling network during axis formation. Genes Dev. 2000;14:1146–1155. [PMC free article] [PubMed] [Google Scholar]
- [115].Mbikay M, Tadros H, Ishida N, Lerner CP, De Lamirande E, Chen A, El-Alfy M, Clermont Y, Seidah NG, Chretien M, Gagnon C, Simpson EM. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci U S A. 2002;99:10293–10298. doi: 10.1073/pnas.162352599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [116].Milner JM, Rowan AD, Elliott SF, Cawston TE. Inhibition of furin-like enzymes blocks interleukin-1alpha/oncostatin M-stimulated cartilage degradation. Arthritis Rheum. 2003;48:1057–1066. doi: 10.1002/art.10873. [DOI] [PubMed] [Google Scholar]
