Furin at the cutting edge: From protein traffic to embryogenesis and disease

Nature Reviews Molecular Cell Biology

Volumn 3, Issue 10, 2002, Pages 753-766

  Thomas, Gary ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FURIN; PROTEIN PRECURSOR;

ALZHEIMER DISEASE; ANTHRAX; BIOCHEMISTRY; CANCER; CATALYSIS; CELLULAR DISTRIBUTION; EMBRYO DEVELOPMENT; ENZYME ACTIVITY; ENZYME STRUCTURE; ENZYME SUBSTRATE; IN VIVO STUDY; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN PROCESSING; PROTEIN TARGETING; REVIEW; VIRUS HEMORRHAGIC FEVER;

AMINO ACID SEQUENCE; DISEASE; EMBRYONIC AND FETAL DEVELOPMENT; ENDOCYTOSIS; FURIN; GOLGI APPARATUS; HOMEOSTASIS; HUMANS; MODELS, BIOLOGICAL; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; NEOPLASM METASTASIS; SIGNAL TRANSDUCTION; SUBTILISINS; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR-ALPHA;

ANTHRAX;

EID: 0036791359     PISSN: 14710072     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrm934     Document Type: Review

References (170)

1. Seidah, N. G., Day, R., Mercinkiewicz, M. & Chretien, M. Precursor convertases: an evolutionary ancient, cell-specific, combinatorial mechanism yielding diverse bioactive peptides and proteins. Ann. N. Y. Acad. Sci. 839, 9-24 (1998).
2. Thacker, C. & Rose, A. M. A look at the Caenorhabditis elegans Kex2/Subtilisin-like proprotein convertase family. Bioessays 22, 545-553 (2000).
3. Zhou, A., Martin, S., Lipkind, G., LaMendola, J. & Steiner, D. F. Regulatory roles of the P domain of the subtilisin-like prohormone convertases. J. Biol. Chem. 273, 11107-11114 (1998).
4. Siezen, R. J., Creemers, J. W. & Van de Ven, W. J. Homology modelling of the catalytic domain of human furin. A model for the eukaryotic subtilisin-like proprotein convertases. Eur. J. Biochem. 222, 255-266 (1994).
5. Rockwell, N. C. & Fuller, R. S. Specific modulation of Kex2/Furin family proteases by potassium. J. Biol. Chem. 277, 17531-17537 (2002).
6. Molloy, S. S., Bresnahan, P. A., Leppla, S. H., Klimpel, K. R. & 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. 267, 16396-16402 (1992).
7. Walker, J. A. et al. Sequence specificity of furin, a proprotein-processing endoprotease, for the hemagglutinin of a virulent avian influenza virus. J. Virol. 68, 1213-1218 (1994).
8. Krysan, D. J., Rockwell, N. C. & Fuller, R. S. Quantitative characterization of furin specificity. Energetics of substrate discrimination using an internally consistent set of hexapeptidyl methylcoumarinamides. J. Biol. Chem. 274, 23229-23234 (1999).
9. Siezen, R. J. Modelling and engineering of enzyme/substrate interactions in subtilisin-like enzymes of unknown 3-dimensional structure. Adv. Exp. Med. Biol. 379, 63-73 (1996).
10. Molloy, S. S. & Thomas, G. in The Enzymes 199-235 (Academic Press, San Diego, CA, 2001).
11. Komiyama, T. & Fuller, R. S. Engineered eglin c variants inhibit yeast and human proprotein processing proteases Kex2 and furin. Biochemistry 39, 15156-15165 (2000).
12. Cameron, A., Appel, J., Houghten, R. A. & Lindberg, I. Polyarginines are potent furin inhibitors. J. Biol. Chem. 275, 36741-36749 (2000).
13. Jean, F. et al. α1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc. Natl. Acad. Sci. U. S. A. 95, 7293-7298 (1998).
14. Anderson, E. D., Thomas, L., Hayflick, J. S. & Thomas, G. Inhibition of HIV-1 gp160-dependent membrane fusion by a furin-directed α1-antitrypsin variant. J. Biol. Chem. 268 24887-24891 (1993).
15. Anderson, E. D. et al. The ordered and compartment-specific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation. J. Biol. Chem. 277, 12879-12890 (2002).
16. Baker, D. Metastable states and folding free energy barriers. Nature Struct. Biol. 5, 1021-1024 (1998).
17. Peters, R. J. et al. Pro region C-terminus:protease active site interactions are critical in catalyzing the folding of α-lytic protease. Biochemistry 37, 12058-12067 (1998).
18. Shinde, U. & Inouye, M. Folding pathway mediated by ar intramolecular chaperone: characterization of the structural changes in pro-subtilisin E coincident with autoprocessing. J. Mol. Biol. 252, 25-30 (1995).
19. Yabuta, Y., Takagi, H., Inouye, M. & Shinde, U. Folding pathway mediated by an intramolecular chaperone: propeptide release modulates activation precision of prosubtilisin. J. Biol. Chem. 276, 44427-44434 (2001).
20. Griffiths, G. & Simons, K. The trans Golgi network: sorting at the exit site of the Golgi complex. Science 234, 438-443 (1986).
21. Gu, F., Crump, C. M. & Thomas, G. Trans-Golgi network sorting. Cell Mol. Life Sci. 58, 1067-1084 (2001).
22. Molloy, S. S., Anderson, E. D., Jean, F. & Thomas, G. Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends Cell Biol. 9, 28-35 (1999).
23. Molloy, S. S., Thomas, L., VanSlyke, J. K., Stenberg, P. E. & Thomas, G. Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface. EMBO J. 13, 18-33 (1994).
24. Bosshart, H. et al. The cytoplasmic domain mediates localization of furin to the trans-Golgi network en route to the endosomal/lysosomal system. J. Cell Biol. 126, 1157-1172 (1994).
25. Schafer, W. et al. Two independent targeting signals in the cytoplasmic domain determine trans-Golgi network localization and endosomal trafficking of the proprotein convertase furin. EMBO J. 14, 2424-2435 (1995).
26. Jones, B. G. et al. Intracellular trafficking of furin is modulated by the phosphorylation state of a casein kinase II site in its cytoplasmic tail. EMBO J. 14, 5869-5883 (1995).
27. Takahashi, S. et al. Localization of furin to the trans-Golgi network and recycling from the cell surface involves Ser and Tyr residues within the cytoplasmic domain. J. Biol. Chem. 270, 28397-28401 (1995).
28. Wan, L. et al. PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell 94, 205-216 (1998).
29. Jung, L. J., Kreiner, T. & Scheller, R. H. Expression of mutant ELH prohormones in AtT-20 cells: the relationship between prohormone processing and sorting. J. Cell Biol. 121, 11-21 (1993).
30. Vischer, U. M. & Wagner, D. D. von Willebrand factor proteolytic processing and multimerization precede the formation of Weibel-Palade bodies. Blood 83, 3536-3544 (1994).
31. Chen, C. D. et al. Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca(2+) stabilization. EMBO J. 20, 6277-6287 (2001).
32. Band, A. M., Maatta, J., Kaariainen, L. & Kuismanen, E. Inhibition of the membrane fusion machinery prevents exit from the TGN and proteolytic processing by furin. FEBS Lett. 505, 118-124 (2001).
33. Simmen, T., Nobile, M., Bonifacino, J. S. & Hunziker, W. Basolateral sorting of furin in MDCK cells requires a phenylalanine-isoleucine motif together with an acidic amino acid cluster. Mol. Cell. Biol. 19, 3136-3144 (1999).
34. Simmen, T., Honing, S., Icking, A., Tikkanen, R. & Hunziker, W. AP-4 binds basolateral signals and participates in basolateral sorting in epithelial MDCK cells. Nature Cell Biol. 4, 154-159 (2002).
35. Folsch, H., Ohno, H., Bonifacino, J. S. & Mellman, I. A novel clathrin adaptor complex mediates basolateral targeting in polarized epithelial cells. Cell 99, 189-198 (1999).
36. Folsch, H., Pypaert, M., Schu, P. & Mellman, I. Distribution and function of AP-1 clathrin adaptor complexes in polarized epithelial cells. J. Cell Biol. 152, 595-606 (2001).
37. Teuchert, M. et al. Sorting of furin at the trans-Golgi network. Interaction of the cytoplasmic tail sorting signals with AP-1 Golgi-specific assembly proteins. J. Biol. Chem. 274, 8199-8207 (1999).
38. Jacobsen, L. et al. The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines minimum requirements for GGA binding. FEBS Lett. 511, 155-158 (2002).
39. Misra, S., Puertollano, R., Kato, Y., Bonifacino, J. S. & Hurley, J. H. Structural basis for acidic-cluster-dileucine sorting-signal recognition by VHS domains. Nature 415, 933-937 (2002).
40. Zhu, Y., Doray, B., Poussu, A., Lehto, V. P. & Kornfeld, S. Binding of GGA2 to the lysosomal enzyme sorting motif of the mannose 6-phosphate receptor. Science 292, 1716-1718 (2001).
41. Crump, C. M. et al. PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic, EMBO J. 20, 2191-2201 (2001).
42. Meyer, C. et al. mu1A-adaptin-deficient mice: lethality, loss of AP-1 binding and rerouting of mannose 6-phosphate receptors. EMBO J. 19, 2193-2203 (2000).
43. Xiang, Y., Molloy, S. S., Thomas, L. & Thomas, G. The PC6B cytoplasmic domain contains two acidic clusters that direct sorting to distinct trans-Golgi network/endosomal compartments. Mol. Biol. Cell 11, 1257-1273 (2000).
44. Piguet, V. et al. HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes. Nature Cell Biol. 2, 163-167 (2000).
45. Nielsen, M. S. et al. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. EMBO J. 20, 2180-2190 (2001).
46. Nakagawa, T. et al. A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 Complex. Cell 103, 569-581 (2000).
47. Liu, G. et al. Cytoskeletal protein ABP-280 directs the intracellular trafficking of furin and modulates proprotein processing in the endocytic pathway. J. Cell Biol. 139, 1719-1733 (1997).
48. Stossel, T. P. et al. Filamins as integrators of cell mechanics and signalling. Nature Rev. Mol. Cell Biol. 2, 138-145 (2001).
49. Barr, V. A., Phillips, S. A., Taylor, S. I. & Haft, C. R. Overexpression of a novel sorting nexin, SNX15, affects endosome morphology and protein trafficking. Traffic 1, 904-916 (2000).
50. Molloy, S. S., Thomas, L., Kamibayashi, C., Mumby, M. C. & Thomas, G. Regulation of endosome sorting by a specific PP2A isoform. J. Cell Biol. 142, 1399-1411 (1998).
51. Mallet, W. G. & Maxfield, F. R. Chimeric forms of furin and TGN38 are transported with the plasma membrane in the trans-Golgi network via distinct endosomal pathways. J. Cell Biol. 146, 345-359 (1999).
52. Varlamov, O., Kalinina, E., Che, F. Y. & Fricker, L. D. Protein phosphatase 2A binds to the cytoplasmic tail of carboxypeptidase D and regulates post-trans-Golgi network trafficking. J. Cell Sci. 114, 311-322 (2001).
53. Urbe, S., Page, L. J. & Tooze, S. A. Homotypic fusion of immature secretory granules during maturation in a cell-free assay. J. Cell Biol. 143, 1831-1844 (1998).
54. Tooze, S. A. Biogenesis of secretory granules in the trans- Golgi network of neuroendocrine and endocrine cells. Biochim. Biophys. Acta 1404, 231-244 (1998).
55. Rudolf, R., Salm, T., Rustom, A. & Gerdes, H. H. Dynamics of immature secretory granules: role of cytoskeletal elements during transport, cortical restriction, and F-actin-dependent tethering. Mol. Biol. Cell 12, 1353-1365 (2001).
56. Eaton, B. A., Haugwitz, M., Lau, D. & Moore, H. P. Biogenesis of regulated exocytotic carriers in neuroendocrine cells. J. Neurosci. 20, 7334-7344 (2000).
57. Littleton, J. T., Serano, T. L., Rubin, G. M., Ganetzky, B. & Chapman, E. R. Synaptic function modulated by changes in the ratio of synaptotagmin I and IV. Nature 400, 757-760 (1999).
58. Dittie, A. S., Thomas, L., Thomas, G. & Tooze, S. A. Interaction of furin in immature secretory granules from neuroendocrine cells with the AP-1 adaptor complex is modulated by casein kinase II phosphorylation. EMBO J. 16, 4859-4870 (1997).
59. Varlamov, O. & Fricker, L. D. Intracellular trafficking of metallocarboxypeptidase D in AtT-20 cells: localization to the trans-Golgi network and recycling from the cell surface. J. Cell Sci. 111, 877-885 (1998).
60. Varlamov, O., Eng, F. J., Novikova, E. G. & Fricker, L. D. Localization of metallocarboxypeptidase D in AtT-20 cells. Potential role in prohormone processing. J. Biol. Chem. 274, 14759-14767 (1999).
61. Waites, C. L. et al. An acidic motif retains vesicular monoamine transporter 2 on large dense core vesicles. J. Cell Biol. 152, 1159-1168 (2001).
62. Paquet, L. et al. The neuroendocrine precursor 7B2 is a sulfated protein proteolytically processed by a ubiquitous furin-like convertase. J. Biol. Chem. 269, 19279-19285 (1994).
63. Canaff, L., Bennett, H. P., Hou, Y., Seidah, N. G. & Hendy, G. N. Proparathyroid hormone processing by the proprotein convertase-7: comparison with furin and assessment of modulation of parathyroid convertase messenger ribonucleic acid levels by calcium and 1,25-dihydroxyvitamin D3. Endocrinology 140, 3633-3642 (1999).
64. Eskeland, N. L. et al. Chromogranin A processing and secretion: specific role of endogenous and exogenous prohormone convertases in the regulated secretory pathway. J. Clin. Invest. 98, 148-156 (1996).
65. Klumperman, J. et al. Cell type-specific sorting of neuropeptides: a mechanism to modulate peptide composition of large dense-core vesicles J. Neurosci. 16, 7930-7940 (1996).
66. Lee, R., Kermani, P., Teng, K. K. & Hempstead, B. L. Regulation of cell survival by secreted proneurotrophins. Science 294, 1945-1948 (2001).
67. Mumm, J. S. et al. A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1. Mol. Cell 5, 197-206 (2000).
68. Bush, G. et al. Ligand-induced signaling in the absence of furin processing of Notch1. Dev. Biol. 229, 494-502 (2001).
69. Isacson, O., Seo, H., Lin, L., Albeck, D. & Granholm, A. C. Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh. Trends Neurosci. 25, 79-84 (2002).
70. Walter, J., Kaether, C., Steiner, H. & Haass, C. The cell biology of Alzheimer's disease: uncovering the secrets of secretases. Curr Opin. Neurobiol. 11, 585-590 (2001).
71. Weidemann, A. et al. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell 57, 115-126 (1989).
72. Luo, J. J., Wallace, M. S., Hawver, D. B., Kusiak, J. W. & Wallace, W. C. Characterization of the neurotrophic interaction between nerve growth factor and secreted α-amyloid precursor protein. J. Neurosci. Res. 63, 410-420 (2001).
73. Wang, H. Y. et al. β-Amyloid(1-42) binds to α7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. J. Biol. Chem. 275, 5625-5632 (2000).
74. Lammich, S. et al. Constitutive and regulated α-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. U.S.A. 96, 3922-3927 (1999).
75. Buxbaum, J. D. et al. Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27765-27767 (1998).
76. Anders, A., Gilbert, S., Garten, W., Postina, R. & Fahrenholz, F. Regulation of the α-secretase ADAM10 by its prodomain and proprotein convertases. FASEB J. 15, 1837-1839 (2001).
77. Lopez-Perez, E. et al. Constitutive α-secretase cleavage of the β-amyloid precursor protein in the furin-deficient LoVo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10. J. Neurochem. 76, 1532-1539 (2001).
78. Bennett, B. D. et al. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's β-secretase. J. Biol. Chem. 276, 37712-37717 (2000).
79. Benjannet, S. at al. Post-translational processing of β-secretase (β-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-β production. J. Biol. Chem. 276, 10879-10887 (2001).
80. Creemers, J. W. et al. Processing of β-secretase by furin and other members of the proprotein convertase family. J. Biol. Chem. 276, 4211-4217 (2001).
81. Walter, J. at al. Phosphorylation regulates intracellular trafficking of β-secretase. J. Biol. Chem. 276, 14634-14641 (2001).
82. Pastorino, L., Ikin, A. F., Nairn, A. C., Pursnani, A. & Buxbaum, J. D. The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total Aβ. Mol. Cell Neurosci. 19, 175-185 (2002).
83. Kim, S. H. et al. Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Nature Neurosci. 2, 984-988 (1999).
84. Kim, S. H., Creemers, J. W., Chu, S., Thinakaran, G. & Sisodia, S. S. Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides. J. Biol. Chem. 277, 1872-1877 (2002).
85. Vidal, R. et al. A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399, 776-781 (1999).
86. Lee, W. M. & Galbraith, R. V. The extracellular actin- scavenger system and actin toxicity. N. Engl. J. Med. 326, 1335-1341 (1992).
87. Maury, C. P. et al. Danish type gelsolin related amyloidosis: 654G-T mutation is associated with a disease pathogenetically and clinically similar to that caused by the 654G-A mutation (familial amyloidosis of the Finnish type). J. Clin. Pathol. 53, 95-99 (2000).
88. Grell, M. et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83, 793-802 (1995).
89. Chen, Y. et al. Mutations within a furin consensus sequence block proteolytic release of ectodysplasin-A and cause X-linked hypohidrotic ectodermal dysplasia. Proc. Natl Acad. Sci. U.S.A. 98, 7218-7223 (2001).
90. Schneider, P. et al. Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A. J. Biol. Chem. 276, 18819-18827 (2001).
91. Tucker, A. S. et al. Edar/Eda interactions regulate enamel knot formation in tooth morphogenesis. Development 121, 4691-4700 (2000).
92. Schneider, P. et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J. Exp. Med. 189, 1747-1756 (1999).
93. Lopez-Fraga, M., Fernandez, R., Albar, J. P. & Hahne, M. Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase. EMBO Rep. 2, 945-951 (2001).
94. Vaux, D. L. The buzz about BAFF. J. Clin. Invest. 109, 17-18 (2002).
95. Roebroek, A. J. et al. Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin. Development 125, 4863-4876 (1998).
96. Constam, D. B. & Robertson, E. J. Tissue-specific requirements for the proprotein convertase furin/SPC1 during embryonic turning and heart looping. Development 127, 245-254 (2000).
97. Dubois, C. M. et al. Evidence that furin is an authentic transforming growth factor-β1-converting enzyme. Am. J. Pathol. 158, 305-316 (2001).
98. Cui, Y., Jean, F., Thomas, G. & Christian, J. L. BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development. EMBO J. 17, 4735-4743 (1998).
99. Cui, Y. et al. The activity and signaling range of mature BMP-4 is regulated by sequential cleavage at two sites within the prodomain of the precursor Genes Dev. 15, 2797-2802 (2001).
100. Gonzalez-Reyes, L. 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. 98, 9859-9864 (2001).
101. Zimmer, G., Budz, L. & Herder, G. Proteolytic activation of respiratory syncytial virus fusion protein. Cleavage at two furin consensus sequences. J. Biol. Chem. 276, 31642-31650 (2001).
102. Blanchette, F. et al. Cross-talk between the p42/p44 MAP kinase and Smad pathways in transforming growth factor β 1-induced furin gene transactivation. J. Biol. Chem. 276, 33986-33994 (2001).
103. Blanchette, F., Rudd, P., Grondin, F., Attisano, L. & Dubois, C. M. Involvement of Smads in TGFβ1-induced furin (fur) transcription. J. Cell. Physiol. 188, 264-273 (2001).
104. Blanchette, F., Day, R., Dong, W., Laprise, M. H. & Dubois, C. M. TGFβ1 regulates gene expression of its own converting enzyme turin. J. Clin. Invest. 99, 1974-1983 (1997).
105. Yamanishi, Y. at al. Expression and regulation of aggrecanase in arthritis: the role of TGF-β. J. Immunol. 168, 1405-1412 (2002).
106. Tang, B. L. ADAMTS: a novel family of extracellular matrix proteases, Int. J. Biochem. Cell. Biol. 33, 33-44 (2001).
107. Mbikay, M., Sirois, F., Yao, J., Seidah, N. G. & Chretien, M. Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. Br. J. Cancer 75, 1509-1514 (1997).
108. Bassi, D. E. et al, Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. Mol. Carcinog. 31, 224-232 (2001).
109. Bassi, D. E. et al. Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells. Proc. Natl Acad. Sci. U.S.A. 98, 10326-10331 (2001).
110. Sounni, N. E. et al. Expression of membrane type 1 matrix metalloproteinase (MT1-MMP) in A2058 melanoma cells is associated with MMP-2 activation and increased tumor growth and vascularization. Int. J Cancer 98, 23-28 (2002).
111. Yana, I. & Weiss, S. J. Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases. Mol. Biol. Cell 11, 2387-2401 (2000).
112. Kang, T., Nagase, H. & Pei, D. Activation of membrane- type matrix metalloproteinase 3 zymogen by the proprotein convertase furin in the trans-Golgi network. Cancer Res. 62, 675-681 (2002).
113. Aznavoorian, S. et al. Membrane type I-matrix metalloproteinase-mediated degradation of type I collagen by oral squamous cell carcinoma cells. Cancer Res. 61, 6264-6275 (2001).
114. Kheradmand, F., Rishi, K. & Werb, Z Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J. Cell Sci. 115, 839-848 (2002).
115. Wu, Y., Yakar, S., Zhao, L., Hennighausen, L. & LeRoith, D. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis Cancer Res. 62, 1030-1035 (2002).
116. Khatib, A. M. et al. 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 (2001).
117. Cheng, M. et al. Pro-protein convertase gene expression in human breast cancer. Int. J Cancer 71, 966-971 (1997).
118. Mahloogi, H., Bassi, D. E. & Klein-Szanto, A. J. Malignant conversion of non-tumorogenic murine skin keritinocytes overexpressing PACE4. Carcinogenesis 23, 565-572 (2002).
119. Klimpel, K. R., Molloy, S. S., Thomas, G. & Leppla, S. H. Anthrax toxin protective antigen is activated by a cell surface protease with the sequence specificity and catalytic properties of furin. Proc. Natl Acad. Sci. U.S.A. 89, 10277-10281 (1992).
120. Jernigan, J. A. et al. Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States Emerg. Infect. Dis. 7, 933-944 (2001).
121. Abrami, L. et al. The pore-forming toxin proaerolysin is activated by furin. J Biol. Chem. 273, 32656-32661 (1998).
122. Gordon, V. M., Benz, R., Fujii, K., Leppla, S. H. & Tweten, R. K. Clostridium septicum α-toxin is proteolytically activated by furin. Infect. Immun. 65, 4130-4134 (1997).
123. Mock, M. & Fouet, A. Anthrax. Annu. Rev. Microbiol. 55, 647-671 (2001).
124. Bradley, K. A., Mogridge, J., Mourez, M., Collier, R. J. & Young, J. A. Identification of the cellular receptor for anthrax toxin. Nature 414, 225-229 (2001).
125. Beauregard, K. E., Collier, R. J. & Swanson, J. A. Proteolytic activation of receptor-bound anthrax protective antigen on macrophages promotes its internalization. Cell. Microbiol. 2, 251-258 (2000).
126. Gordon, V. M., Klimpel, K. R., Arora, N., Henderson, M. A. & Leppla, S. H. Proteolytic activation of bacterial toxins by eukaryotic cells is performed by furin and by additional cellular proteases. Infect. Immun. 63, 82-87 (1995).
127. Sellman, B. R., Mourez, M. & Collier, R. J. Dominant- negative mutants of a toxin subunit: an approach to therapy of anthrax. Science 292, 695-697 (2001).
128. Ballard, J., Sokolov, Y., Yuan, W. L., Kagan, B. L & Tweten, R. K. Activation and mechanism of Clostridium septicum α toxin. Mol. Microbiol. 10, 627-634 (1993).
129. Schiavo, G. & van der Goot, F. G. The bacterial toxin toolkit. Nature Rev. Mol. Cell Biol. 2, 530-537 (2001).
130. Wedekind, J. E. et al. Refined crystallographic structure of Pseudomonas aeruginosa exotoxin A and its implications for the molecular mechanism of toxicity. J. Mol. Biol. 314, 823-837 (2001).
131. 2-terminal region across planar bilayers. J. Gen. Physiol. 112, 317-324 (1998).
132. Girod, A. et al. Evidence for a COP-1-independent transport route from the Golgi complex to the endoplasmic reticulum Nature Cell Biol. 1, 423-430 (1999).
133. Jackson, M. E. et al. The KDEL retrieval system is exploited by Pseudomonas exotoxin A, but not by Shiga-like toxin-1, during retrograde transport from the Golgi complex to the endoplasmic reticulum. J. Cell Sci. 112, 467-475 (1999).
134. Storrie, B. et al. Recycling of Golgi-resident glycosyltransferases through the ER reveals a novel pathway and provides an explanation for nocodazole-induced Golgi scattering. J. Cell Biol. 143, 1505-1521 (1998).
135. Bass, J., Turck, C., Rouard, M. & Steiner, D. F. Furin-mediated processing in the early secretory pathway: sequential cleavage and degradation of misfolded insulin receptors. Proc. Natl Acad. Sci. U.S.A. 97, 11905-11909 (2000).
136. Moulard, M. & Decroly, E. Maturation of HIV envelope glycoprotein precursors by cellular endoproteases. Biochim. Biophys. Acta 1469, 121-132 (2000).
137. Ohnishi, Y. et al. A furin-defective cell line is able to process correctly the gp 160 of human immunodeficiency virus type 1. J. Virol. 68, 4075-4079 (1994).
138. Binley, J. M. et al. Enhancing the proteolytic maturation of human immunodeficiency virus type 1 envelope glycoproteins. J Virol. 76, 2606-2616 (2002).
139. Zambon, M. C. The pathogenesis of influenza in humans. Rev. Med. Virol. 11, 227-241 (2001).
140. Takada, A. & Kawaoka, Y. The pathogenesis of Ebola hemorrhagic fever. Trends Microbiol. 9, 506-511 (2001).
141. Feldmann, H., Volchkov, V. E., Volchkova, V. A. & Klenk, H. D. The glycoproteins of Marburg and Ebola virus and their potential roles in pathogenesis. Arch. Virol. Suppl. 15, 159-169 (1999).
142. Rott, R., Klenk, H. D., Nagai, Y. & Tashiro, M. Influenza viruses, cell enzymes, and pathogenicity. Am. J. Respir. Crit. Care Med. 152, S16-19 (1995).
143. Hatta, M., Gao, P., Halfmann, P. & Kawaoka, Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 298, 1840-1842 (2001).
144. Horimoto, T. & Kawaoka, Y. Pandemic threat posed by avian influenza A viruses. Clin. Microbiol. Rev. 14, 129-149 (2001).
145. Volchkov, V. E., Feldmann, H., Volchkova, V. A. & Klenk, H. D. Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proc. Natl Acad. Sci. U.S.A. 95, 5762-5767 (1998).
146. Neumann, G., Feldmann, H., Watanabe, S., Lukashevich, I. & Kawaoka, Y. Reverse genetics demonstrates that proteolytic processing of the Ebola virus glycoprotein is not essential for replication in cell culture. J. Virol. 76, 406-410 (2002).
147. Heinz, F. X. & Allison, S. L. The machinery for flavivirus fusion with host cell membranes. Curr. Opin. Microbiol. 4, 450-455 (2001).
148. Simmons, G., Wool-Lewis, R. J., Baribaud, F., Netter, R. C. & Bates, P. Ebola virus glycoproteins induce global surface protein down-modulation and loss of cell adherence. J. Virol. 76, 2516-2528 (2002).
149. Yang, Z. Y. et al. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nature Med. 6, 886-889 (2000).
150. Zhou, A., Webb, G., Zhu, X. & Steiner, D. F. Proteolytic processing in the secretory pathway. J. Biol. Chem. 274, 20745-20748 (1999).
151. Seidan, N. G. & Chretien, M. Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res 848, 45-62 (1999).
152. Steiner, D. F., Cunningham, D., Spigelman, L. & Aten, B. Insulin biosynthesis: evidence for a precursor. Science 157, 697-700 (1967).
153. Steiner, D. F. et al. Proinsulin and the biosynthesis of insulin. Recent Prog. Horm. Res. 25, 207-282 (1969).
154. Chretien, M. & Li, C. H. Isolation, purification, and characterization of γ-lipotropic hormone from sheep pituitary glands. Can. J. Biochem. 45, 1163-1174 (1967).
155. 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-α-factor. Cell 37, 1075-1089 (1984).
156. Thomas, G. et al. Yeast KEX2 endopeptidase correctly cleaves a neuroendocrine prohormone in mammalian cells. Science 241, 226-230 (1988).
157. Roebroek, A. J. et al. 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 (1986).
158. Fuller, R. S., Brake, A. J. & Thorner, J. Intracellular targeting and structural conservation of a prohormone- processing endoprotease. Science 246, 482-486 (1989).
159. Bresnahan, P. A. et al. Human fur gene encodes a yeast KEX2-like endoproteese that cleaves pro-β-NGF in vivo. J. Cell Biol. 111, 2851-2859 (1990).
160. Wise, R. J. et al. Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site. Proc. Natl Acad. Sci. U.S.A. 87, 9378-9382 (1990).
161. From the Centers for Disease Control and Prevention. Update: investigation of bioterrorism-related Anthrax - Connecticut, 2001. JAMA 287, 34-35 (2002).
162. Update: Investigation of bioterrorism related anthrax- Connecticut, 2001. M. M. W R. Moth. Mortal. Wkl. Rep. 50, 1077-1079 (2001).
163. Duesbery, N. S. & Vande Woude, G. F. Anthrax toxins. Cell. Mol. Life Sci. 55, 1599-1609 (1999).
164. Constam, D. B. & Robertson, E. J. SPC4/PACE4 regulates a TGFβ signaling network during axis formation. Genes Dev. 14, 1146-1155 (2000).
165. Furuta, M. et al. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc. Natl Acad Sci. U.S.A. 94, 6646-6651 (1997).
166. Mbikay, M. et al. Impaired fertility in mice deficient for the testicular germ-cell protease PC4. Proc. Natl Acad. Sci. U.S.A. 94, 6842-6846 (1997).
167. Constam, D. B. & Robertson, E. J. Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J. Cell Biol. 144, 139-149 (1999).
168. Zhu, X. et al. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Natl Acad. Sci. U.S.A. 99, 10293-10298 (2002).
169. Jackson, R. S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genet. 16, 303-306 (1997).
170. Steiner, D F. The proprotein convertases. Curr. Opin. Chem. Biol. 2, 31-39 (1998).