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The proprotein convertases are potential targets in the treatment of dyslipidemia

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Abstract

The family of the secretory proprotein convertases (PCs) comprises seven basic amino acid (aa)-specific subtilisin-like serine proteinases known as PC1/3, PC2, furin, PC4, PC5/6, PACE4 and PC7, and two other PCs, SKI-1 (subtilisin-kexin isozyme-1)/S1P (site-1 protease) and PCSK9 (proprotein convertase subtilisin kexin 9) that cleave at nonbasic residues. Except for the testicular PC4, all the other convertases are expressed in brain and peripheral organs and play a critical role in various functions including the production of diverse neuropeptides as well as growth factors and receptors, the regulation of cellular adhesion/migration, cholesterol and fatty acid homeostasis, and growth/differentiation of progenitor cells. Some of these convertases process proteins that are implicated in pathologies, including cancer malignancies, tissue regeneration, and viral infections. The implication of some of these convertases in sterol/lipid metabolism has only recently been appreciated. SKI-1/S1P activates the synthesis of cholesterol and fatty acids as well as the LDL receptor (LDLR), whereas PCSK9 inactivates the LDLR. Moreover, furin, PC5 and/or, PACE4 inactivates endothelial and lipoprotein lipases. Humans and mice exhibiting either a gain or loss of function of PCSK9 through specific point mutations or knockouts develop hypercholesterolemia and hypocholesterolemia phenotypes, respectively. A PCSK9 inhibitor in combination with statins offers a most promising therapeutic target to treat cardiovascular disorders including dyslipidemias. Specific inhibitors/modulators of the other PCs should find novel therapeutic applications in the control of PC-regulated pathologies.

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References

  1. 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 (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34:154–156

    Article  PubMed  CAS  Google Scholar 

  2. Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabes JP (2005) Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat 26:497

    Article  PubMed  Google Scholar 

  3. Anderson ED, Molloy SS, Jean F, Fei H, Shimamura S, Thomas G (2002) The ordered and compartment-specfific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation. J Biol Chem 277:12879–12890

    Article  PubMed  CAS  Google Scholar 

  4. Attie AD (2004) The mystery of PCSK9. Arterioscler Thromb Vasc Biol 24:1337–1339

    Article  PubMed  CAS  Google Scholar 

  5. Attie AD, Seidah NG (2005) Dual regulation of the LDL receptor-some clarity and new questions. Cell Metab 1:290–292

    Article  PubMed  CAS  Google Scholar 

  6. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366:1267–1278

    Article  PubMed  CAS  Google Scholar 

  7. Barrett AJ (2004) Bioinformatics of proteases in the MEROPS database. Curr Opin Drug Discov Devel 7:334–341

    PubMed  CAS  Google Scholar 

  8. Basak A, Chretien M, Seidah NG (2002) A rapid fluorometric assay for the proteolytic activity of SKI-1/S1P based on the surface glycoprotein of the hemorrhagic fever Lassa virus. FEBS Lett 514:333–339

    Article  PubMed  CAS  Google Scholar 

  9. Bassi DE, Fu J, Lopez DC, Klein-Szanto AJ (2005) Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol Carcinog 44:151–161

    Article  PubMed  CAS  Google Scholar 

  10. Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chretien M, Prat A, Seidah NG (2004) NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem 279:48865–48875

    Article  PubMed  CAS  Google Scholar 

  11. Benjannet S, Rhainds D, Hamelin J, Nassoury N, Seidah NG (2006) The proprotein convertase PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. J Biol Chem 281:30561–30572

    Article  PubMed  CAS  Google Scholar 

  12. Berge KE, Ose L, Leren TP (2006) Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol 26:1094–10100

    Article  PubMed  CAS  Google Scholar 

  13. Bergeron E, Basak A, Decroly E, Seidah NG (2003) Processing of alpha4 integrin by the proprotein convertases: histidine at position P6 regulates cleavage. Biochem J 373:475–484

    Article  PubMed  CAS  Google Scholar 

  14. Briel M, Nordmann AJ, Bucher HC (2005) Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses. Curr Opin Lipidol 16:601–605

    Article  PubMed  CAS  Google Scholar 

  15. Broedl UC, Jin W, Rader DJ (2004) Endothelial lipase: a modulator of lipoprotein metabolism upregulated by inflammation. Trends Cardiovasc Med 14:202–206

    Article  PubMed  CAS  Google Scholar 

  16. Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340

    Article  PubMed  CAS  Google Scholar 

  17. Brown MS, Goldstein JL (2006) Biomedicine. Lowering LDL—not only how low, but how long? Science 311:1721–1723

    Article  PubMed  CAS  Google Scholar 

  18. Cameron J, Holla OL, Ranheim T, Kulseth MA, Berge KE, Leren TP (2006) Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet 15:1551–1558

    Article  PubMed  CAS  Google Scholar 

  19. Carmena R, Duriez P, Fruchart JC (2004) Atherogenic lipoprotein particles in atherosclerosis. Circulation 109:III2–III7

    Article  PubMed  CAS  Google Scholar 

  20. Cheng D, Espenshade PJ, Slaughter CA, Jaen JC, Brown MS, Goldstein JL (1999) Secreted site-1 protease cleaves peptides corresponding to luminal loop of sterol regulatory element-binding proteins. J Biol Chem 274:22805–22812

    Article  PubMed  CAS  Google Scholar 

  21. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37:161–165

    Article  PubMed  CAS  Google Scholar 

  22. Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B, Jarnoux AL, Grefhorst A, Staels B, Krempf M (2006) Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element binding protein 1c. J Biol Chem 281:6211–6218

    Article  PubMed  CAS  Google Scholar 

  23. Creemers JW, Siezen RJ, Roebroek AJ, Ayoubi TA, Huylebroeck D, Van de Ven WJ (1993) Modulation of furin-mediated proprotein processing activity by site-directed mutagenesis. J Biol Chem 268:21826–21834

    PubMed  CAS  Google Scholar 

  24. De Bie I, Marcinkiewicz M, Malide D, Lazure C, Nakayama K, Bendayan M, Seidah NG (1996) The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments. J Cell Biol 135:1261–1275

    Article  PubMed  Google Scholar 

  25. Dickson MC, Slager HG, Duffie E, Mummery CL, Akhurst RJ (1993) RNA and protein localisations of TGF beta 2 in the early mouse embryo suggest an involvement in cardiac development. Development 117:625–639

    PubMed  CAS  Google Scholar 

  26. Dubois CM, Blanchette F, Laprise MH, Leduc R, Grondin F, Seidah NG (2001) Evidence that furin is an authentic transforming growth factor-beta1-converting enzyme. Am J Pathol 158:305–316

    PubMed  CAS  Google Scholar 

  27. Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (2004) Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 24:1454–1459

    Article  PubMed  CAS  Google Scholar 

  28. Dunker N, Krieglstein K (2000) Targeted mutations of transforming growth factor-beta genes reveal important roles in mouse development and adult homeostasis. Eur J Biochem 267:6982–6988

    Article  PubMed  CAS  Google Scholar 

  29. Elagoz A, Benjannet S, Mammarbassi A, Wickham L, Seidah NG (2002) Biosynthesis and cellular trafficking of the convertase SKI-1/S1P: ectodomain shedding requires SKI-1 activity. J Biol Chem 277:11265–11275

    Article  PubMed  CAS  Google Scholar 

  30. Essalmani R, Hamelin J, Marcinkiewicz J, Chamberland A, Mbikay M, Chretien M, Seidah NG, Prat A (2006) Deletion of the gene encoding proprotein convertase 5/6 causes early embryonic lethality in the mouse. Mol Cell Biol 26:354–361

    Article  PubMed  CAS  Google Scholar 

  31. Falchi M, Andrew T, Snieder H, Swaminathan R, Surdulescu GL, Spector TD (2005) Identification of QTLs for serum lipid levels in a female sib-pair cohort: a novel application to improve the power of two-locus linkage analysis. Hum Mol Genet 14:2971–2979

    Article  PubMed  CAS  Google Scholar 

  32. Fasano T, Cefalu AB, Di Leo E, Noto D, Pollaccia D, Bocchi L, Valenti V, Bonardi R, Guardamagna O, Averna M, Tarugi P (2007) A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol (in press)

  33. Gotto AM Jr, Pownall HJ, Havel RJ (1986) Introduction to the plasma lipoproteins. Methods Enzymol 128:3–41

    PubMed  CAS  Google Scholar 

  34. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR (2007) The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis (in press)

  35. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 100:12027–12032

    Article  PubMed  CAS  Google Scholar 

  36. Jean F, Stella K, Thomas L, Liu G, Xiang Y, Reason AJ, Thomas G (1998) Alpha1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc Natl Acad Sci USA 95:7293–7298

    Article  PubMed  CAS  Google Scholar 

  37. Jin W, Fuki IV, Seidah NG, Benjannet S, Glick JM, Rader DJ (2005) Proprotein covertases are responsible for proteolysis and inactivation of endothelial lipase. J Biol Chem 280:36551–36559

    Article  PubMed  CAS  Google Scholar 

  38. Jin W, Millar JS, Broedl U, Glick JM, Rader DJ (2003) Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo. J Clin Invest 111:357–362

    Article  PubMed  CAS  Google Scholar 

  39. Jonas A (2002) Lipoprotein structure. In: Vance DE, Vance JE (eds) Biochemistry of lipids, lipoproteins and membranes. Elsevier, Amsterdam, pp 483–504

    Chapter  Google Scholar 

  40. Khatib AM, Siegfried G, Chretien M, Metrakos P, Seidah NG (2002) Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. Am J Pathol 160:1921–1935

    PubMed  CAS  Google Scholar 

  41. Khatib AM, Siegfried G, Prat A, Luis J, Chretien M, Metrakos P, Seidah NG (2001) 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 276:30686–30693

    Article  PubMed  CAS  Google Scholar 

  42. Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, Horikoshi H, Furukawa H (2002) Angptl3 regulates lipid metabolism in mice. Nat Genet 30:151–157

    Article  PubMed  CAS  Google Scholar 

  43. Koster A, Chao YB, Mosior M, Ford A, Gonzalez-DeWhitt PA, Hale JE, Li D, Qiu Y, Fraser CC, Yang DD, Heuer JG, Jaskunas SR, Eacho P (2005) Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 146:4943–4950

    Article  PubMed  CAS  Google Scholar 

  44. Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, Hobbs HH (2006) A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 78:410–422

    Article  PubMed  CAS  Google Scholar 

  45. Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, Anderson NN, Ho YK, Hammer RE, Horton JD (2006) Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and inlivers of parabiotic mice. J Clin Invest 116:2995–3005

    Article  PubMed  CAS  Google Scholar 

  46. Lalanne F, Lambert G, Amar MJ, Chetiveaux M, Zair Y, Jarnoux AL, Ouguerram K, Friburg J, Seidah NG, Brewer HB Jr, Krempf M, Costet P (2005) Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J Lipid Res 46:1312–1319

    Article  PubMed  CAS  Google Scholar 

  47. Lambert G, Jarnoux AL, Pineau T, Pape O, Chetiveaux M, Laboisse C, Krempf M, Costet P (2006) Fasting induces hyperlipidemia in mice overexpressing PCSK9: lack of modulation of VLDL hepatic output by the LDLr. Endocrinology 147:4985–4995

    Article  PubMed  CAS  Google Scholar 

  48. Leduc R, Molloy SS, Thorne BA, Thomas G (1992) Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage. J Biol Chem 267:14304–14308

    PubMed  CAS  Google Scholar 

  49. Lenz O, ter Meulen J, Klenk HD, Seidah NG, Garten W (2001) The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P. Proc Natl Acad Sci USA 98:12701–12705

    Article  PubMed  CAS  Google Scholar 

  50. Leren TP (2004) Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 65:419–422

    Article  PubMed  CAS  Google Scholar 

  51. Lewis GF, Rader DJ (2005) New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 96:1221–1232

    Article  PubMed  CAS  Google Scholar 

  52. Lissitzky JC, Luis J, Munzer JS, Benjannet S, Parat F, Chretien M, Marvaldi J, Seidah NG (2000) 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 346(Pt 1):133–138

    Article  PubMed  CAS  Google Scholar 

  53. Lu R, Yang P, O’Hare P, Misra V (1997) Luman, a new member of the CREB/ATF family, binds to herpes simplex virus VP16-associated host cellular factor. Mol Cell Biol 17:5117–5126

    PubMed  CAS  Google Scholar 

  54. Lusson J, Vieau D, Hamelin J, Day R, Chretien M, Seidah NG (1993) 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 USA 90:6691–6695

    Article  PubMed  CAS  Google Scholar 

  55. Maxwell KN, Breslow JL (2004) Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA 101:7100–7105

    Article  PubMed  CAS  Google Scholar 

  56. Maxwell KN, Fisher EA, Breslow JL (2005) Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA 102:2069–2074

    Article  PubMed  CAS  Google Scholar 

  57. Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (2003) Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 44:2109–2119

    Article  PubMed  CAS  Google Scholar 

  58. Mercure C, Jutras I, Day R, Seidah NG, Reudelhuber TL (1996) Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex. Hypertension 28:840–846

    PubMed  CAS  Google Scholar 

  59. Mitchell KJ, Pinson KI, Kelly OG, Brennan J, Zupicich J, Scherz P, Leighton PA, Goodrich LV, Lu X, Avery BJ, Tate P, Dill K, Pangilinan E, Wakenight P, Tessier-Lavigne M, Skarnes WC (2001) Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet 28:241–249

    Article  PubMed  CAS  Google Scholar 

  60. Molloy SS, Thomas L, VanSlyke JK, Stenberg PE, Thomas G (1994) Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface. EMBO J 13:18–33

    PubMed  CAS  Google Scholar 

  61. Mouchantaf R, Watt HL, Sulea T, Seidah NG, Alturaihi H, Patel YC, Kumar U (2004) Prosomatostatin is proteolytically processed at the amino terminal segment by subtilase SKI-1. Regul Pept 120:133–140

    Article  PubMed  CAS  Google Scholar 

  62. Nakagawa T, Hosaka M, Torii S, Watanabe T, Murakami K, Nakayama K (1993) 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) 113:132–135

    CAS  Google Scholar 

  63. Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK (2005) Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 25:2654–2660

    Article  PubMed  CAS  Google Scholar 

  64. Nassoury N, Blasiole D, Tebon-Oler A, Benjannet S, Poupon VSM, McPherson P, Attie AD, Prat A, Seidah NG (2007) The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic (in press)

  65. Nour N, Basak A, Chretien M, Seidah NG (2003) Structure-function analysis of the prosegment of the proprotein convertase PC5A. J Biol Chem 278:2886–2895

    Article  PubMed  CAS  Google Scholar 

  66. Nour N, Mayer G, Mort JS, Salvas A, Mbikay M, Morrison CJ, Overall CM, Seidah NG (2005) 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 16:5215–5226

    Article  PubMed  CAS  Google Scholar 

  67. Olsson AG (2006) Are lower levels of low-density lipoprotein cholesterol beneficial? a review of recent data. Curr Atheroscler Rep 8:382–389

    Article  PubMed  CAS  Google Scholar 

  68. Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M (2004) Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler Thromb Vasc Biol 24:1448–1453

    Article  PubMed  CAS  Google Scholar 

  69. Overall CM, Kleifeld O (2006) Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer 94:941–946

    Article  PubMed  CAS  Google Scholar 

  70. Park SW, Moon YA, Horton JD (2004) Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 279:50630–50638

    Article  PubMed  CAS  Google Scholar 

  71. Pasquato A, Pullikotil P, Asselin MC, Vacatello M, Paolillo L, Ghezzo F, Basso F, Di Bello C, Dettin M, Seidah NG (2006) The proprotein convertase SKI-1/S1P: in vitro analysis of lassa virus glycoprotein-derived substrates and ex vivo validation of irreversible peptide inhibitors. J Biol Chem 281:23471–23481

    Article  PubMed  CAS  Google Scholar 

  72. Pisciotta L, Oliva CP, Cefalu AB, Noto D, Bellocchio A, Fresa R, Cantafora A, Patel D, Averna M, Tarugi P, Calandra S, Bertolini S (2006) Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis 186:433–440

    Article  PubMed  CAS  Google Scholar 

  73. Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (2003) Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 4:544–558

    Article  PubMed  CAS  Google Scholar 

  74. Pullikotil P, Vincent M, Nichol ST, Seidah NG (2004) Development of protein-based inhibitors of the proprotein of convertase SKI-1/S1P: processing of SREBP-2, ATF6, and a viral glycoprotein. J Biol Chem 279:17338–17347

    Article  PubMed  CAS  Google Scholar 

  75. Raman M, Cobb MH (2006) TGF-beta regulation by Emilin1: new links in the etiology of hypertension. Cell 124:893–895

    Article  PubMed  CAS  Google Scholar 

  76. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, Hammer RE, Moon YA, Horton JD (2005) Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA 102:5374–5379

    Article  PubMed  CAS  Google Scholar 

  77. Reudelhuber TL, Ramla D, Chiu L, Mercure C, Seidah NG (1994) Proteolytic processing of human prorenin in renal and non-renal tissues. Kidney Int 46:1522–1524

    Article  PubMed  CAS  Google Scholar 

  78. Roebroek AJ, Schalken JA, Bussemakers MJ, van Heerikhuizen H, Onnekink C, Debruyne FM, Bloemers HP, Van de Ven WJ (1986) Characterization of human c-fes/fps reveals a new transcription unit (fur) in the immediately upstream region of the proto-oncogene. Mol Biol Rep 11:117–125

    Article  PubMed  CAS  Google Scholar 

  79. Roebroek AJ, Taylor NA, Louagie E, Pauli I, Smeijers L, Snellinx A, Lauwers A, Van de Ven WJ, Hartmann D, Creemers JW (2004) Limited redundancy of the proprotein convertase furin in mouse liver. J Biol Chem 279:53442–53450

    Article  PubMed  CAS  Google Scholar 

  80. Roebroek AJ, Umans L, Pauli IG, Robertson EJ, van Leuven F, Van de Ven WJ, Constam DB (1998) Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin. Development 125:4863–4876

    PubMed  CAS  Google Scholar 

  81. Sakai J, Rawson RB, Espenshade PJ, Cheng D, Seegmiller AC, Goldstein JL, Brown MS (1998) Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell 2:505–514

    Article  PubMed  CAS  Google Scholar 

  82. Salvas A, Benjannet S, Reudelhuber TL, Chretien M, Seidah NG (2005) Evidence for proprotein convertase activity in the endoplasmic reticulum/early Golgi. FEBS Lett 579:5621–5625

    PubMed  CAS  Google Scholar 

  83. Scamuffa N, Calvo F, Chretien M, Seidah NG, Khatib AM (2006) Proprotein convertases: lessons from knockouts. FASEB J 20:1954–1963

    Article  PubMed  CAS  Google Scholar 

  84. Schlombs K, Wagner T, Scheel J (2003) Site-1 protease is required for cartilage development in zebrafish. Proc Natl Acad Sci USA 100:14024–14029

    Article  PubMed  CAS  Google Scholar 

  85. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003) The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 100:928–933

    Article  PubMed  CAS  Google Scholar 

  86. Seidah NG, Chretien M (1999) Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res 848:45–62

    Article  PubMed  CAS  Google Scholar 

  87. Seidah NG, Chretien M, Day R (1994) The family of subtilisin/kexin like pro-protein and pro-hormone convertases: divergent or shared functions. Biochimie 76:197–209

    Article  PubMed  CAS  Google Scholar 

  88. Seidah NG, Khatib AM, Prat A (2006) The proprotein convertases and their implication in sterol and/or lipid metabolism. Biol Chem 387:871–877

    Article  PubMed  CAS  Google Scholar 

  89. 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 (1999) Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization. Proc Natl Acad Sci USA 96:1321–1326

    Article  PubMed  CAS  Google Scholar 

  90. Seidah NG, Prat A (2002) Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem 38:79–94

    PubMed  CAS  Google Scholar 

  91. Shioji K, Mannami T, Kokubo Y, Inamoto N, Takagi S, Goto Y, Nonogi H, Iwai N (2004) Genetic variants in PCSK9 affect the cholesterol level in Japanese. J Hum Genet 49:109–114

    Article  PubMed  CAS  Google Scholar 

  92. Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chretien M, Seidah NG, Khatib AM (2003) The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest 111:1723–1732

    Article  PubMed  CAS  Google Scholar 

  93. Siegfried G, Basak A, Prichett-Pejic W, Scamuffa N, Ma L, Benjannet S, Veinot JP, Calvo F, Seidah N, Khatib AM (2005) Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases. Oncogene 24:6925–6935

    Article  PubMed  CAS  Google Scholar 

  94. Siegfried G, Khatib AM, Benjannet S, Chretien M, Seidah NG (2003) 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 63:1458–1463

    PubMed  CAS  Google Scholar 

  95. Srour N, Lebel A, McMahon S, Fournier I, Fugere M, Day R, Dubois CM (2003) TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity. FEBS Lett 554:275–283

    Article  PubMed  CAS  Google Scholar 

  96. Stawowy P, Blaschke F, Kilimnik A, Goetze S, Kallisch H, Chretien M, Marcinkiewicz M, Fleck E, Graf K (2002) Proprotein convertase PC5 regulation by PDGF-BB involves PI3-kinase/p70(s6)-kinase activation in vascular smooth muscle cells. Hypertension 39:399–404

    Article  PubMed  CAS  Google Scholar 

  97. Stawowy P, Fleck E (2005) Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels. J Mol Med 83:865–875

    Article  PubMed  CAS  Google Scholar 

  98. Stawowy P, Graf K, Goetze S, Roser M, Chretien M, Seidah NG, Fleck E, Marcinkiewicz M (2003) Coordinated regulation and colocalization of alphav integrin and its activating enzyme proprotein convertase PC5 in vivo. Histochem Cell Biol 119:239–245

    PubMed  CAS  Google Scholar 

  99. Stawowy P, Kallisch H, Kilimnik A, Margeta C, Seidah NG, Chretien M, Fleck E, Graf K (2004) Proprotein convertases regulate insulin-like growth factor 1-induced membrane-type 1 matrix metalloproteinase in VSMCs via endoproteolytic activation of the insulin-like growth factor-1 receptor. Biochem Biophys Res Commun 321:531–538

    Article  PubMed  CAS  Google Scholar 

  100. Stawowy P, Kallisch H, Veinot JP, Kilimnik A, Prichett W, Goetze S, Seidah NG, Chretien M, Fleck E, Graf K (2004) Endoproteolytic activation of alpha(v) integrin by proprotein convertase PC5 is required for vascular smooth muscle cell adhesion to vitronectin and integrin-dependent signaling. Circulation 109:770–776

    Article  PubMed  CAS  Google Scholar 

  101. Stawowy P, Marcinkiewicz J, Graf K, Seidah N, Chretien M, Fleck E, Marcinkiewicz M (2001) Selective expression of the proprotein convertases furin, pc5, and pc7 in proliferating vascular smooth muscle cells of the rat aorta in vitro. J Histochem Cytochem 49:323–332

    PubMed  CAS  Google Scholar 

  102. Stawowy P, Margeta C, Kallisch H, Seidah NG, Chretien M, Fleck E, Graf K (2004) Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-beta1 involves furin-convertase. Cardiovasc Res 63:87–97

    Article  PubMed  CAS  Google Scholar 

  103. Stirling J, O’Hare P (2006) CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P. Mol Biol Cell 17:413–426

    Article  PubMed  CAS  Google Scholar 

  104. Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, Soutar AK (2005) Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum Mol Genet 14:1161–1169

    Article  PubMed  CAS  Google Scholar 

  105. Tadros H, Seidah NG, Chretien M, Mbikay M (2002) Genetic mapping of the gene for SKI-1/S1P protease (locus symbol Mbtps1) to mouse chromosome 8. DNA Seq 13:109–111

    PubMed  CAS  Google Scholar 

  106. Takahashi S, Nakagawa T, Kasai K, Banno T, Duguay SJ, Van de Ven WJ, Murakami K, Nakayama K (1995) 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 270:26565–26569

    Article  PubMed  CAS  Google Scholar 

  107. Tall AR (2006) Protease variants, LDL, and coronary heart disease. N Engl J Med 354:1310–1312

    Article  PubMed  CAS  Google Scholar 

  108. Taylor NA, Van de Ven WJ, Creemers JW (2003) Curbing activation: proprotein convertases in homeostasis and pathology. FASEB J 17:1215–1227

    Article  PubMed  CAS  Google Scholar 

  109. Thomas G (2002) Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3:753–766

    Article  PubMed  CAS  Google Scholar 

  110. Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM (2004) A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 114:349–353

    Article  PubMed  CAS  Google Scholar 

  111. Toth PP, Davidson MH (2005) Cholesterol absorption blockade with ezetimibe. Curr Drug Targets Cardiovasc Haematol Disord 5:455–462

    Article  PubMed  CAS  Google Scholar 

  112. Toure BB, Munzer JS, Basak A, Benjannet S, Rochemont J, Lazure C, Chretien M, Seidah NG (2000) Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. J Biol Chem 275:2349–2358

    Article  PubMed  CAS  Google Scholar 

  113. Twisk J, Gillian-Daniel DL, Tebon A, Wang L, Barrett PH, Attie AD (2000) The role of the LDL receptor in apolipoprotein B secretion. J Clin Invest 105:521–532

    Article  PubMed  CAS  Google Scholar 

  114. Yang J, Goldstein JL, Hammer RE, Moon YA, Brown MS, Horton JD (2001) Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc Natl Acad Sci USA 98:13607–13612

    Article  PubMed  CAS  Google Scholar 

  115. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364

    Article  PubMed  CAS  Google Scholar 

  116. Zacchigna L, Vecchione C, Notte A, Cordenonsi M, Dupont S, Maretto S, Cifelli G, Ferrari A, Maffei A, Fabbro C, Braghetta P, Marino G, Selvetella G, Aretini A, Colonnese C, Bettarini U, Russo G, Soligo S, Adorno M, Bonaldo P, Volpin D, Piccolo S, Lembo G, Bressan GM (2006) Emilin1 links TGF-beta maturation to blood pressure homeostasis. Cell 124:929–942

    Article  PubMed  CAS  Google Scholar 

  117. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79:514–523

    Article  PubMed  CAS  Google Scholar 

  118. Zheng M, Streck RD, Scott RE, Seidah NG, Pintar JE (1994) The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity. J Neurosci 14:4656–4673

    PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Brigitte Mary for her secretarial help. This work was supported by grants from the CIHR (MOP 36496, MGP-44363, and Canada chair no. 201652) and by a generous gift from the Strauss foundation.

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  1. Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, Quebec, H2W 1R7, Canada

    Nabil G. Seidah & Annik Prat

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  1. Nabil G. Seidah
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Correspondence to Nabil G. Seidah.

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Seidah, N.G., Prat, A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J Mol Med 85, 685–696 (2007). https://doi.org/10.1007/s00109-007-0172-7

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