Proprotein convertases in health and disease

New England Journal of Medicine

Volumn 365, Issue 26, 2011, Pages 2507-2518

  Artenstein, Andrew W ^a   Opal, Steven M ^b  

^a MEMORIAL HOSPITAL OF RHODE ISLAND   (United States)

^b BROWN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FURIN; PROPROTEIN CONVERTASE 1; PROPROTEIN CONVERTASE 2; PROPROTEIN CONVERTASE 4; PROPROTEIN CONVERTASE 5B; PROPROTEIN CONVERTASE 6; PROPROTEIN CONVERTASE 7; PROPROTEIN CONVERTASE 9; PROPROTEIN CONVERTASE SKI 1; SERINE PROTEINASE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ATHEROSCLEROSIS; CORRELATIONAL STUDY; DIARRHEA; DISEASE PREDISPOSITION; DWARFISM; EMBRYOPATHY; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME DEFICIENCY; ENZYME SPECIFICITY; ENZYME STRUCTURE; ENZYME SYNTHESIS; GLUCOSE HOMEOSTASIS; GROWTH RETARDATION; HUMAN; HYPERLIPIDEMIA; HYPERPHAGIA; HYPOCHOLESTEROLEMIA; HYPOGLYCEMIA; HYPOGONADOTROPIC HYPOGONADISM; INFECTION; INFERTILITY; MALABSORBTIVE DIARRHEA; MALIGNANT NEOPLASTIC DISEASE; METABOLIC SYNDROME X; METASTASIS POTENTIAL; MULTIPLE MALFORMATION SYNDROME; OBESITY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN PROCESSING; REVIEW; CHEMISTRY; COMMUNICABLE DISEASE; ENZYMOLOGY; NEOPLASM; PHYSIOLOGY;

ALZHEIMER DISEASE; COMMUNICABLE DISEASES; HUMANS; HYPERLIPIDEMIAS; NEOPLASMS; PROPROTEIN CONVERTASES;

EID: 84855393059     PISSN: 00284793     EISSN: 15334406     Source Type: Journal    
DOI: 10.1056/NEJMra1106700     Document Type: Review

References (111)

1. Page MJ, Di Cera E. Serine peptidases: classification, structure and function. Cell Mol Life Sci 2008;65:1220-36.
2. Di Cera E. Serine proteases. IUBMB Life 2009;61:510-5.
3. Steiner DF, Cunningham D, Spigelman L, Aten B. Insulin biosynthesis: evidence for a precursor. Science 1967;157: 697-700.
4. Van de Ven WJM, Voorberg J, Fontijn R, et al. Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Mol Biol Rep 1990;14:265-75.
5. Molloy SS, Anderson ED, Jean F, Thomas G. Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends Cell Biol 1999;9:28-35. (Pubitemid 29138669)
6. Sakai J, Rawson RB, Espenshade PJ, et al. Molecular identification of the sterolregulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell 1998;2:505-14. (Pubitemid 128381303)
7. Seidah NG, Mowla SJ, Hamelin J, et al. Mammalian subtilisin/kexin isoenzyme SKI-1: a widely expressed proprotein convertase with a unique cleavage specificity and cellular localization. Proc Natl Acad Sci U S A 1999;96:1321-6. (Pubitemid 29098449)
8. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 2003;100:928-33. (Pubitemid 36183932)
9. Thomas G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 2002;3:753-66.
10. 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;267:14304-8.
11. Anderson ED, Molloy SS, Jean F, Fei H, Shimamura S, Thomas G. The ordered and compartment-specific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation. J Biol Chem 2002;277:12879-90. (Pubitemid 34952654)
12. Creemers JWM, Vey M, Schäfer W, et al. Endoproteolytic cleavage of its propeptide is a prerequisite for efficient transport of furin out of the endoplasmic reticulum. J Biol Chem 1995;270:2695-702.
13. Henrich S, Cameron A, Bourenkov GP, et al. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Nat Struct Biol 2003;10:520-6. [Erratum, Nat Struct Biol 2003;10:669.] (Pubitemid 36792902)
14. Henrich S, Lindberg I, Bode W, Than ME. Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity. J Mol Biol 2005;345:211-27. (Pubitemid 39574845)
15. Creemers JWM, Siezen RJ, Roebroek AJM, Ayoubi TAY, Huylebroeck D, Van de Ven WJM. Modulation of furin-mediated proprotein processing activity by site-directed mutagenesis. J Biol Chem 1993; 268:21826-34. (Pubitemid 23320684)
16. Creemers JWM, Khatib AM. Knock-out mouse models of proprotein convertases: unique functions or redundancy? Front Biosci 2008;13:4960-71. (Pubitemid 351599650)
17. Seidah NG, Chrétien M. Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res 1999;848:45-62. (Pubitemid 30001653)
18. Duckert P, Brunak S, Blom N. Prediction of proprotein convertase cleavage sites. Protein Eng Des Sel 2004;17:107-12. (Pubitemid 38173174)
19. Seidah NG, Mayer G, Zaid A, et al. The activation and physiological functions of the proprotein convertases. Int J Biochem Cell Biol 2008;40:1111-25.
20. Jean F, Basak A, Rondeau N, et al. Enzymic characterization of murine and human prohormone convertase-1 (mPC1 and hPC1) expressed in mammalian GH4C1 cells. Biochem J 1993;292:891-900. (Pubitemid 23210226)
21. Shennan KIJ, 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;270:1402-7.
22. Molloy SS, Bresnahan PA, Leppla SH, Klimpel KR, Thomas G. Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen. J Biol Chem 1992;267: 16396-402.
23. Basak A, Touré BB, Lazure C, Mbikay M, Chrétien M, Seidah NG. Enzymic characterization in vitro of recombinant proprotein convertase PC4. Biochem J 1999; 343:29-37. (Pubitemid 29473874)
24. Cain BM, Vishnuvardhan D, Wang W, et al. Production, purification, and characterization of recombinant prohormone covertase 5 from baculovirus-infected insect cells. Protein Expr Purif 2002;24:227-33. (Pubitemid 40047439)
25. De Bie I, Marcinkiewicz M, Malide D, et al. The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments. J Cell Biol 1996;135: 1261-75. (Pubitemid 27014598)
26. Tsuji A, Hashimoto E, Ikoma T, et al. Inactivation of proprotein convertase, PACE4, by a1-antitrypsin Portland (a1-PDX), a blocker of proteolytic activation of bone morphogenetic protein during embryogenesis: evidence that PACE4 is able to form an SDS-stable acyl intermediate with a1-PDX. J Biochem 1999;126:591-603. (Pubitemid 29452626)
27. Munzer JS, Basak A, Zhong M, et al. In vitro characterization of the novel proprotein convertase PC7. J Biol Chem 1997;272:19672-81. [Erratum, J Biol Chem 1997;272:30589.] (Pubitemid 27340055)
28. Touré BB, Munzer JS, Basak A, et al. Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. J Biol Chem 2000;275:2349-58. (Pubitemid 30081992)
29. Naureckiene S, Ma L, Sreekumar K, et al. Functional characterization of Narc 1, a novel proteinase related to proteinase K. Arch Biochem Biophys 2003;420:55-67. (Pubitemid 37393374)
30. Kirschner M, Gerhart J. Evolvability. Proc Natl Acad Sci U S A 1998;95:8420-7. (Pubitemid 28350502)
31. Scamuffa N, Calvo F, Chrétien M, Seidah NG, Khatib AM. Proprotein convertases: lessons from knockouts. FASEB J 2006;20:1954-63. (Pubitemid 44953895)
32. Zhu X, Zhou A, Dey A, et al. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci U S A 2002;99:10293-8.
33. O'Rahilly S, Gray H, Humphreys PJ, et al. Impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med 1995;333:1386-90.
34. Jackson RS, Creemers JWM, Ohagi S, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997;16:303-6. (Pubitemid 27280217)
35. Jackson RS, Creemers JWM, Farooqi IS, et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 2003;112:1550-60. (Pubitemid 38056281)
36. Farooqi IS, Volders K, Stanhope R, et al. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab 2007;92:3369-73. (Pubitemid 47435306)
37. Furuta M, Yano H, Zhou A, et al. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc Natl Acad Sci U S A 1997;94:6646-51. (Pubitemid 27281918)
38. Roebroek AJM, Umans L, Pauli IGL, et al. Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase furin. Development 1998;125: 4863-76. (Pubitemid 29026768)
39. Roebroek AJ, Taylor NA, Louagie E, et al. Limited redundancy of the proprotein convertase furin in mouse liver. J Biol Chem 2004;279:53442-50. (Pubitemid 40051849)
40. Szumska D, Pieles G, Essalmani R, et al. VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes Dev 2008;22:1465-77. (Pubitemid 351793081)
41. Constam DB, Robertson EJ. SPC4/ PACE4 regulates a TGFβ signaling network during axis formation. Genes Dev 2000;14:1146-55. (Pubitemid 30324427)
42. 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;134:181-91. (Pubitemid 26231529)
43. Lloyd DJ, Bohan S, Gekakis N. Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum Mol Genet 2006;15:1884-93. [Erratum, Hum Mol Genet 2008;17:3435.] (Pubitemid 43821779)
44. Hoshino A, Kowalska D, Jean F, Lazure C, Lindberg I. Modulation of PC1/3 activity by self-interaction and substrate binding. Endocrinology 2011;152:1402-11.
45. Bassi DE, Fu J, de Cicco RL, Klein-Szanto AJP. Proprotein convertases: "master switches" in the regulation of tumor growth and progression. Mol Carcinog 2005;44:151-61. (Pubitemid 41552748)
46. Bassi DE, Mahloogi H, Lopez De Cicco R, Klein-Szanto A. Increased furin activity enhances the malignant phenotype of human head and neck cancer cells. Am J Pathol 2003;162:439-47. (Pubitemid 36267851)
47. Mercapide J, Lopez De Cicco R, Bassi DE, Castresana JS, Thomas G, Klein-Szanto AJ. Inhibition of furin-mediated processing results in suppression of astrocytoma cell growth and invasiveness. Clin Cancer Res 2002;8:1740-6. (Pubitemid 34633729)
48. Konoshita T, Gasc JM, Villard E, et al. Expression of PC2 and PC1/PC3 in human pheochromocytomas. Mol Cell Endocrinol 1994;99:307-14. (Pubitemid 24076980)
49. Takumi I, Steiner DF, Sanno N, Teramoto A, Osamura RY. Localization of prohormone convertases 1/3 and 2 in the human pituitary gland and pituitary adenomas: analysis by immunohistochemistry, immunoelectron microscopy, and laser scanning microscopy. Mod Pathol 1998; 11:232-8. (Pubitemid 28131531)
50. Kajiwara H, Itoh Y, Itoh J, Yasuda M, Osamura RY. Immunohistochemical expressions of prohormone convertase (PC) 1/3 and PC2 in carcinoids of various organs. Tokai J Exp Clin Med 1999;24:13-20.
51. Creemers JWM, Roebroek AJM, Van de Ven WJM. Expression in human lung tumor cells of the proprotein processing enzyme PC1/PC3: cloning and primary sequence of a 5kb cDNA. FEBS Lett 1992; 300:82-8.
52. Mbikay M, Sirois F, Yao J, Seidah NG, Chrétien M. Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. Br J Cancer 1997;75:1509-14. (Pubitemid 27196874)
53. Bassi DE, Mahloogi H, Al-Saleem L, Lopez De Cicco R, Ridge JA, Klein-Szanto AJP. Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. Mol Carcinog 2001;31: 224-32. (Pubitemid 32831348)
54. Cheng M, Watson PH, Paterson JA, Seidah N, Chrétien M, Shiu RPC. Pro-protein convertase gene expression in human breast cancer. Int J Cancer 1997;71:966-71. (Pubitemid 27252877)
55. Khatib AM, Siegfried G, Prat A, et al. Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells. J Biol Chem 2001;276:30686-93.
56. Hubbard FC, Goodrow TL, Liu SC, et al. Expression of PACE4 in chemically induced carcinomas is associated with spindle cell tumor conversion and increased invasive ability. Cancer Res 1997;57:5226-31. (Pubitemid 27516353)
57. Mahloogi H, Bassi DE, Klein-Szanto AJP. Malignant conversion of non-tumorigenic murine skin keratinocytes overexpressing PACE4. Carcinogenesis 2002;23: 565-72. (Pubitemid 34498492)
58. Pesu M, Watford WT, Wei L, et al. T cell-expressed proprotein convertase furin is essential for maintenance of peripheral tolerance. Nature 2008;455:246-50.
59. Dubois CM, Blanchette F, Laprise MH, Luduc R, Grondin F, Seidah NG. Evidence that furin is an authentic transforming growth factor-β1- converting enzyme. Am J Pathol 2001;158:305-16. (Pubitemid 32096497)
60. Arsenault D, Lucien F, Dubois CM. Hypoxia enhances cancer cell invasion through relocalization of the proprotein convertase furin from the trans-Golgi network to the cell surface. J Cell Physiol 2011 April 18 (Epub ahead of print).
61. 5 integrin. J Biol Chem 2000;275:33308-13.
62. Siegfried G, Basak A, Cromlish JA, et al. The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest 2003; 111:1723-32. (Pubitemid 38057753)
63. Bassi DE, Mahloogi H, Klein-Szanto AJP. The proprotein convertases furin and PACE4 play a significant role in tumor progression. Mol Carcinog 2000;28:63-9. (Pubitemid 30432473)
64. Yana I, Weiss SJ. Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases. Mol Biol Cell 2000;11:2387-401. (Pubitemid 30489922)
65. Primakoff P, Myles DG. The ADAM gene family: surface proteins with adhesion and protease activity. Trends Genet 2000;16:83-7. (Pubitemid 30084721)
66. Pei D, Weiss SJ. Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature 1995;375:244-7.
67. Gu M, Gordon VM, Fitzgerald DJP, Leppla SH. Furin regulates both the activation of Pseudomonas exotoxin A and the quantity of the toxin receptor expressed on target cells. Infect Immun 1996;64:524-7. (Pubitemid 26032824)
68. Tsuneoka M, Nakayama K, Hatsuzawa K, Komada M, Kitamura N, Mekada E. Evidence for involvement of furin in cleavage and activation of diphtheria toxin. J Biol Chem 1993;268:26461-5. (Pubitemid 23361724)
69. Lea N, Lord M, Roberts LM. Proteolytic cleavage of the A subunit is essential for maximal cytotoxicity of Escherichia coli 0157:H7 Shiga-like toxin-1. Microbiology 1999;145:999-1004. (Pubitemid 29231802)
70. Young JAT, Collier RJ. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu Rev Biochem 2007;76:243-65.
71. Gordon VM, Rehemtulla A, Leppla SH. A role for PACE4 in the proteolytic activation of anthrax toxin protective antigen. Infect Immun 1997;65:3370-5. (Pubitemid 27342423)
72. Abrami L, Fivaz M, Decroly E, et al. The pore-forming toxin proaerolysin is activated by furin. J Biol Chem 1998;273: 32656-61. (Pubitemid 28557648)
73. Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W. Inhibitionof furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Nature 1992; 360:358-61. (Pubitemid 23000676)
74. Decha P, Rungrotmongkol T, Intharathep P, et al. Source of high pathogenicity of an avian influenza virus H5N1: why H5 is better cleaved by furin. Biophys J 2008; 95:128-34.
75. Hatta M, Gao P, Halfmann P, Kawaoka Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 2001;293:1840-2. (Pubitemid 32845783)
76. González-Reyes L, Ruiz-Argüello MB, García-Barreno B, et al. Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion. Proc Natl Acad Sci U S A 2001;98:9859-64. (Pubitemid 32769394)
77. Watanabe M, Hirano A, Stenglein S, Nelson J, Thomas G, Wong TC. Engineered serine protease inhibitor prevents furin-catalyzed activation of the fusion glycoprotein and production of infectious measles virus. J Virol 1995;69:3206-10.
78. Jean F, Thomas L, Molloy SS, et al. A protein-based therapeutic for human cytomegalovirus infection. Proc Natl Acad Sci U S A 2000;97:2864-9. (Pubitemid 30159263)
79. Volchkov VE, Feldmann H, Volchkova VA, Klenk HD. Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proc Natl Acad Sci U S A 1998;95:5762-7.
80. Volchkov VE, Volchkova VA, Ströher U, et al. Proteolytic processing of Marburg virus glycoprotein. Virology 2000; 268:1-6. (Pubitemid 30131964)
81. Day PM, Schiller JT. The role of furin in papillomavirus infection. Future Microbiol 2009;4:1255-62.
82. McNutt MC, Lagace TA, Horton JD. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J Biol Chem 2007;282:20799-803. (Pubitemid 47099894)
83. Maxwell KN, Breslow JL. Adenoviralmediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A 2004;101:7100-5. (Pubitemid 38596449)
84. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-6. (Pubitemid 36666925)
85. Rashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A 2005;102:5374-9. (Pubitemid 40530265)
86. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006;79:514-23. (Pubitemid 44384260)
87. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-72.
88. Vassar R, Kovacs DM, Yan R, Wong PC. The β-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 2009;29:12787-94.
89. Bennett BD, Denis P, Haniu M, et al. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's β-secretase. J Biol Chem 2000;275:37712-7. [Erratum, J Biol Chem 2001;276:15561.] (Pubitemid 32004885)
90. 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; 73:2056-62. (Pubitemid 29491820)
91. Hwang EM, Kim SK, Sohn JH, et al. Furin is an endogenous regulator of α-secretase associated APP processing. Biochem Biophys Res Commun 2006; 349:654-9. (Pubitemid 44344566)
92. 1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc Natl Acad Sci U S A 1998;95:7293-8.
93. Sarac MS, Cameron A, Lindberg I. The furin inhibitor hexa-D-arginine blocks the activation of Pseudomonas aeruginosa exotoxin A in vivo. Infect Immun 2002; 70:7136-9. (Pubitemid 35387951)
94. Shiryaev SA, Remacle AG, Ratnikov BI, et al. Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens. J Biol Chem 2007;282:20847-53. (Pubitemid 47099910)
95. Komiyama T, Coppola JM, Larsen MJ, et al. Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules. J Biol Chem 2009;284:15729-38.
96. Artenstein AW. Anthrax: from antiquity to answers. J Infect Dis 2007;195:471-3. (Pubitemid 46214388)
97. Remacle AG, Gawlik K, Golubkov VS, et al. Selective and potent furin inhibitors protect cells from anthrax without significant toxicity. Int J Biochem Cell Biol 2010;42:987-95.
98. Opal SM, Artenstein AW, Cristofaro PA, et al. Inter-alpha-inhibitor proteins are endogenous furin inhibitors and provide protection against experimental anthrax intoxication. Infect Immun 2005; 73:5101-5. (Pubitemid 41105669)
99. Opal SM, Lim YP, Cristofaro P, et al. Inter-α inhibitor proteins: a novel therapeutic strategy for experimental anthrax infection. Shock 2011;35:42-4.
100. Lim YP, Bendelja K, Opal SM, Siryaporn E, Hixson DC, Palardy JE. Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis. J Infect Dis 2003;188:919-26. (Pubitemid 37176040)
101. Yang S, Lim YP, Zhou M, et al. Administration of human inter-α-inhibitors maintains hemodynamic stability and improves survival during sepsis. Crit Care Med 2002;30:617-22. (Pubitemid 34214627)
102. Bassi DE, Lopez De Cicco R, Mahloogi H, Zucker S, Thomas G, Klein-Szanto AJP. Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells. Proc Natl Acad Sci U S A 2001;98:10326-31. (Pubitemid 32803019)
103. Basak A, Chen A, Scamuffa N, Mohottalage D, Basak S, Khatib AM. Blockade of furin activity and furin-induced tumor cells malignant phenotypes by the chemically synthesized human furin prodomain. Curr Med Chem 2010;17:2214-21.
104. De Vos L, DeClerq J, Rosas GG, et al. MMTV-cre-mediated fur inactivation concomitant with PLAG1 proto-oncogene activation delays salivary gland tumorigenesis in mice. Int J Oncol 2008;32:1073-83.
105. Sun X, Essalmani R, Seidah NG, Prat A. The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model. Mol Cancer 2009;8:73.
106. Bassi DE, Zhang J, Cenna J, Litwin S, Cukierman E, Klein-Szanto AJP. Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis. Neoplasia 2010;12: 516-26.
107. Coppola JM, Bhojani MS, Ross BD, Rehemtulla A. A small-molecule furin inhibitor inhibits cancer cell motility and invasiveness. Neoplasia 2008;10:363-70. (Pubitemid 351483576)
108. Scamuffa N, Siegfried G, Bontemps Y, et al. Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells. J Clin Invest 2008;118:352-63.
109. Mayer G, Poirier S, Seidah NG. Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J Biol Chem 2008;283:31791-801.
110. Seidah NG. What lies ahead for the proprotein convertases? Ann N Y Acad Sci 2011;1220:149-61.
111. Chan JCY, Piper DE, Cao Q, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A 2009; 106:9820-5.