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. 1995 Jun 1;14(11):2424–2435. doi: 10.1002/j.1460-2075.1995.tb07240.x

Two independent targeting signals in the cytoplasmic domain determine trans-Golgi network localization and endosomal trafficking of the proprotein convertase furin.

W Schäfer 1, A Stroh 1, S Berghöfer 1, J Seiler 1, M Vey 1, M L Kruse 1, H F Kern 1, H D Klenk 1, W Garten 1
PMCID: PMC398356  PMID: 7781597

Abstract

Furin, a subtilisin-like eukaryotic endoprotease, is responsible for proteolytic cleavage of cellular and viral proteins transported via the constitutive secretory pathway. Cleavage occurs at the C-terminus of basic amino acid sequences, such as R-X-K/R-R and R-X-X-R. Furin was found predominantly in the trans-Golgi network (TGN), but also in clathrin-coated vesicles dispatched from the TGN, on the plasma membrane as an integral membrane protein and in the medium as an anchorless enzyme. When furin was vectorially expressed in normal rat kidney (NRK) cells it accumulated in the TGN similarly to the endogenous glycoprotein TGN38, often used as a TGN marker protein. The signals determining TGN targeting of furin were investigated by mutational analysis of the cytoplasmic tail of furin and by using the hemagglutinin (HA) of fowl plague virus, a protein with cell surface destination, as a reporter molecule, in which membrane anchor and cytoplasmic tail were replaced by the respective domains of furin. The membrane-spanning domain of furin grafted to HA does not localize the chimeric molecule to the TGN, whereas the cytoplasmic domain does. Results obtained on furin mutants with substitutions and deletions of amino acids in the cytoplasmic tail indicate that wild-type furin is concentrated in the TGN by a mechanism involving two independent targeting signals, which consist of the acidic peptide CPSDSEEDEG783 and the tetrapeptide YKGL765. The acidic signal in the cytoplasmic domain of a HA-furin chimera is necessary and sufficient to localize the reporter molecule to the TGN, whereas YKGL is a determinant for targeting to the endosomes. The data support the concept that the acidic signal, which is the dominant one, retains furin in the TGN, whereas the YKGL motif acts as a retrieval signal for furin that has escaped to the cell surface.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barr P. J. Mammalian subtilisins: the long-sought dibasic processing endoproteases. Cell. 1991 Jul 12;66(1):1–3. doi: 10.1016/0092-8674(91)90129-m. [DOI] [PubMed] [Google Scholar]
  2. Bos K., Wraight C., Stanley K. K. TGN38 is maintained in the trans-Golgi network by a tyrosine-containing motif in the cytoplasmic domain. EMBO J. 1993 May;12(5):2219–2228. doi: 10.1002/j.1460-2075.1993.tb05870.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bosshart H., Humphrey J., Deignan E., Davidson J., Drazba J., Yuan L., Oorschot V., Peters P. J., Bonifacino J. S. The cytoplasmic domain mediates localization of furin to the trans-Golgi network en route to the endosomal/lysosomal system. J Cell Biol. 1994 Sep;126(5):1157–1172. doi: 10.1083/jcb.126.5.1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brake B., Braghetta P., Banting G., Bressan G., Luzio J. P., Stanley K. K. A new recombinant DNA strategy for the molecular cloning of rare membrane proteins. Biochem J. 1990 May 1;267(3):631–637. doi: 10.1042/bj2670631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bresnahan P. A., Leduc R., Thomas L., Thorner J., Gibson H. L., Brake A. J., Barr P. J., Thomas G. Human fur gene encodes a yeast KEX2-like endoprotease that cleaves pro-beta-NGF in vivo. J Cell Biol. 1990 Dec;111(6 Pt 2):2851–2859. doi: 10.1083/jcb.111.6.2851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bucci C., Parton R. G., Mather I. H., Stunnenberg H., Simons K., Hoflack B., Zerial M. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell. 1992 Sep 4;70(5):715–728. doi: 10.1016/0092-8674(92)90306-w. [DOI] [PubMed] [Google Scholar]
  7. Chakrabarti S., Brechling K., Moss B. Vaccinia virus expression vector: coexpression of beta-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol. 1985 Dec;5(12):3403–3409. doi: 10.1128/mcb.5.12.3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chapman R. E., Munro S. Retrieval of TGN proteins from the cell surface requires endosomal acidification. EMBO J. 1994 May 15;13(10):2305–2312. doi: 10.1002/j.1460-2075.1994.tb06514.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chen W. S., Lazar C. S., Lund K. A., Welsh J. B., Chang C. P., Walton G. M., Der C. J., Wiley H. S., Gill G. N., Rosenfeld M. G. Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation. Cell. 1989 Oct 6;59(1):33–43. doi: 10.1016/0092-8674(89)90867-2. [DOI] [PubMed] [Google Scholar]
  10. Collawn J. F., Stangel M., Kuhn L. A., Esekogwu V., Jing S. Q., Trowbridge I. S., Tainer J. A. Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis. Cell. 1990 Nov 30;63(5):1061–1072. doi: 10.1016/0092-8674(90)90509-d. [DOI] [PubMed] [Google Scholar]
  11. Fuerst T. R., Niles E. G., Studier F. W., Moss B. Eukaryotic transient-expression system based on recombinant vaccinia virus that synthesizes bacteriophage T7 RNA polymerase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8122–8126. doi: 10.1073/pnas.83.21.8122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fuller R. S., Brake A. J., Thorner J. Intracellular targeting and structural conservation of a prohormone-processing endoprotease. Science. 1989 Oct 27;246(4929):482–486. doi: 10.1126/science.2683070. [DOI] [PubMed] [Google Scholar]
  13. Garten W., Stieneke A., Shaw E., Wikstrom P., Klenk H. D. Inhibition of proteolytic activation of influenza virus hemagglutinin by specific peptidyl chloroalkyl ketones. Virology. 1989 Sep;172(1):25–31. doi: 10.1016/0042-6822(89)90103-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gotoh B., Ohnishi Y., Inocencio N. M., Esaki E., Nakayama K., Barr P. J., Thomas G., Nagai Y. Mammalian subtilisin-related proteinases in cleavage activation of the paramyxovirus fusion glycoprotein: superiority of furin/PACE to PC2 or PC1/PC3. J Virol. 1992 Nov;66(11):6391–6397. doi: 10.1128/jvi.66.11.6391-6397.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Griffiths G., Fuller S. D., Back R., Hollinshead M., Pfeiffer S., Simons K. The dynamic nature of the Golgi complex. J Cell Biol. 1989 Feb;108(2):277–297. doi: 10.1083/jcb.108.2.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Griffiths G., Simons K. The trans Golgi network: sorting at the exit site of the Golgi complex. Science. 1986 Oct 24;234(4775):438–443. doi: 10.1126/science.2945253. [DOI] [PubMed] [Google Scholar]
  17. Hallenberger S., Bosch V., Angliker H., Shaw E., Klenk H. D., Garten W. Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Nature. 1992 Nov 26;360(6402):358–361. doi: 10.1038/360358a0. [DOI] [PubMed] [Google Scholar]
  18. Hatsuzawa K., Hosaka M., Nakagawa T., Nagase M., Shoda A., Murakami K., Nakayama K. Structure and expression of mouse furin, a yeast Kex2-related protease. Lack of processing of coexpressed prorenin in GH4C1 cells. J Biol Chem. 1990 Dec 25;265(36):22075–22078. [PubMed] [Google Scholar]
  19. Hatsuzawa K., Murakami K., Nakayama K. Molecular and enzymatic properties of furin, a Kex2-like endoprotease involved in precursor cleavage at Arg-X-Lys/Arg-Arg sites. J Biochem. 1992 Mar;111(3):296–301. doi: 10.1093/oxfordjournals.jbchem.a123753. [DOI] [PubMed] [Google Scholar]
  20. Higuchi R., Krummel B., Saiki R. K. A general method of in vitro preparation and specific mutagenesis of DNA fragments: study of protein and DNA interactions. Nucleic Acids Res. 1988 Aug 11;16(15):7351–7367. doi: 10.1093/nar/16.15.7351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hosaka M., Nagahama M., Kim W. S., Watanabe T., Hatsuzawa K., Ikemizu J., Murakami K., Nakayama K. Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway. J Biol Chem. 1991 Jul 5;266(19):12127–12130. [PubMed] [Google Scholar]
  22. Humphrey J. S., Peters P. J., Yuan L. C., Bonifacino J. S. Localization of TGN38 to the trans-Golgi network: involvement of a cytoplasmic tyrosine-containing sequence. J Cell Biol. 1993 Mar;120(5):1123–1135. doi: 10.1083/jcb.120.5.1123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jackson M. R., Nilsson T., Peterson P. A. Retrieval of transmembrane proteins to the endoplasmic reticulum. J Cell Biol. 1993 Apr;121(2):317–333. doi: 10.1083/jcb.121.2.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jones S. M., Crosby J. R., Salamero J., Howell K. E. A cytosolic complex of p62 and rab6 associates with TGN38/41 and is involved in budding of exocytic vesicles from the trans-Golgi network. J Cell Biol. 1993 Aug;122(4):775–788. doi: 10.1083/jcb.122.4.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Klenk H. D., Garten W., Rott R. Inhibition of proteolytic cleavage of the hemagglutinin of influenza virus by the calcium-specific ionophore A23187. EMBO J. 1984 Dec 1;3(12):2911–2915. doi: 10.1002/j.1460-2075.1984.tb02231.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Klenk H. D., Rott R. The molecular biology of influenza virus pathogenicity. Adv Virus Res. 1988;34:247–281. doi: 10.1016/S0065-3527(08)60520-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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. 1992 Nov 1;89(21):10277–10281. doi: 10.1073/pnas.89.21.10277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Korner J., Chun J., O'Bryan L., Axel R. Prohormone processing in Xenopus oocytes: characterization of cleavage signals and cleavage enzymes. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11393–11397. doi: 10.1073/pnas.88.24.11393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kornfeld S. Trafficking of lysosomal enzymes. FASEB J. 1987 Dec;1(6):462–468. doi: 10.1096/fasebj.1.6.3315809. [DOI] [PubMed] [Google Scholar]
  30. Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kuroda K., Gröner A., Frese K., Drenckhahn D., Hauser C., Rott R., Doerfler W., Klenk H. D. Synthesis of biologically active influenza virus hemagglutinin in insect larvae. J Virol. 1989 Apr;63(4):1677–1685. doi: 10.1128/jvi.63.4.1677-1685.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ladinsky M. S., Howell K. E. The trans-Golgi network can be dissected structurally and functionally from the cisternae of the Golgi complex by brefeldin A. Eur J Cell Biol. 1992 Oct;59(1):92–105. [PubMed] [Google Scholar]
  33. Le Borgne R., Schmidt A., Mauxion F., Griffiths G., Hoflack B. Binding of AP-1 Golgi adaptors to membranes requires phosphorylated cytoplasmic domains of the mannose 6-phosphate/insulin-like growth factor II receptor. J Biol Chem. 1993 Oct 25;268(30):22552–22556. [PubMed] [Google Scholar]
  34. Lehmann L. E., Eberle W., Krull S., Prill V., Schmidt B., Sander C., von Figura K., Peters C. The internalization signal in the cytoplasmic tail of lysosomal acid phosphatase consists of the hexapeptide PGYRHV. EMBO J. 1992 Dec;11(12):4391–4399. doi: 10.1002/j.1460-2075.1992.tb05539.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lusson J., Vieau D., Hamelin J., Day R., Chrétien M., Seidah N. G. 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 Jul 15;90(14):6691–6695. doi: 10.1073/pnas.90.14.6691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Luzio J. P., Banting G. Eukaryotic membrane traffic: retrieval and retention mechanisms to achieve organelle residence. Trends Biochem Sci. 1993 Oct;18(10):395–398. doi: 10.1016/0968-0004(93)90097-7. [DOI] [PubMed] [Google Scholar]
  37. Luzio J. P., Brake B., Banting G., Howell K. E., Braghetta P., Stanley K. K. Identification, sequencing and expression of an integral membrane protein of the trans-Golgi network (TGN38). Biochem J. 1990 Aug 15;270(1):97–102. doi: 10.1042/bj2700097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Machamer C. E., Rose J. K. A specific transmembrane domain of a coronavirus E1 glycoprotein is required for its retention in the Golgi region. J Cell Biol. 1987 Sep;105(3):1205–1214. doi: 10.1083/jcb.105.3.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mackett M., Smith G. L., Moss B. General method for production and selection of infectious vaccinia virus recombinants expressing foreign genes. J Virol. 1984 Mar;49(3):857–864. doi: 10.1128/jvi.49.3.857-864.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Matter K., Hunziker W., Mellman I. Basolateral sorting of LDL receptor in MDCK cells: the cytoplasmic domain contains two tyrosine-dependent targeting determinants. Cell. 1992 Nov 27;71(5):741–753. doi: 10.1016/0092-8674(92)90551-m. [DOI] [PubMed] [Google Scholar]
  41. Mellman I., Simons K. The Golgi complex: in vitro veritas? Cell. 1992 Mar 6;68(5):829–840. doi: 10.1016/0092-8674(92)90027-A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Misumi Y., Oda K., Fujiwara T., Takami N., Tashiro K., Ikehara Y. Functional expression of furin demonstrating its intracellular localization and endoprotease activity for processing of proalbumin and complement pro-C3. J Biol Chem. 1991 Sep 5;266(25):16954–16959. [PubMed] [Google Scholar]
  43. Misumi Y., Sohda M., Ikehara Y. Sequence of the cDNA encoding rat furin, a possible propeptide-processing endoprotease. Nucleic Acids Res. 1990 Nov 25;18(22):6719–6719. doi: 10.1093/nar/18.22.6719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Moehring J. M., Inocencio N. M., Robertson B. J., Moehring T. J. Expression of mouse furin in a Chinese hamster cell resistant to Pseudomonas exotoxin A and viruses complements the genetic lesion. J Biol Chem. 1993 Feb 5;268(4):2590–2594. [PubMed] [Google Scholar]
  45. 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. 1992 Aug 15;267(23):16396–16402. [PubMed] [Google Scholar]
  46. 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. 1994 Jan 1;13(1):18–33. doi: 10.1002/j.1460-2075.1994.tb06231.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Munro S. Sequences within and adjacent to the transmembrane segment of alpha-2,6-sialyltransferase specify Golgi retention. EMBO J. 1991 Dec;10(12):3577–3588. doi: 10.1002/j.1460-2075.1991.tb04924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. 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. 1993 Feb;113(2):132–135. doi: 10.1093/oxfordjournals.jbchem.a124015. [DOI] [PubMed] [Google Scholar]
  49. Nakagawa T., Murakami K., Nakayama K. Identification of an isoform with an extremely large Cys-rich region of PC6, a Kex2-like processing endoprotease. FEBS Lett. 1993 Jul 26;327(2):165–171. doi: 10.1016/0014-5793(93)80163-o. [DOI] [PubMed] [Google Scholar]
  50. Nilsson T., Lucocq J. M., Mackay D., Warren G. The membrane spanning domain of beta-1,4-galactosyltransferase specifies trans Golgi localization. EMBO J. 1991 Dec;10(12):3567–3575. doi: 10.1002/j.1460-2075.1991.tb04923.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Ortmann D., Ohuchi M., Angliker H., Shaw E., Garten W., Klenk H. D. Proteolytic cleavage of wild type and mutants of the F protein of human parainfluenza virus type 3 by two subtilisin-like endoproteases, furin and Kex2. J Virol. 1994 Apr;68(4):2772–2776. doi: 10.1128/jvi.68.4.2772-2776.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Pelham H. R. Control of protein exit from the endoplasmic reticulum. Annu Rev Cell Biol. 1989;5:1–23. doi: 10.1146/annurev.cb.05.110189.000245. [DOI] [PubMed] [Google Scholar]
  53. Pelham H. R. Multiple targets for brefeldin A. Cell. 1991 Nov 1;67(3):449–451. doi: 10.1016/0092-8674(91)90517-3. [DOI] [PubMed] [Google Scholar]
  54. Pfeffer S. R., Rothman J. E. Biosynthetic protein transport and sorting by the endoplasmic reticulum and Golgi. Annu Rev Biochem. 1987;56:829–852. doi: 10.1146/annurev.bi.56.070187.004145. [DOI] [PubMed] [Google Scholar]
  55. Ponnambalam S., Rabouille C., Luzio J. P., Nilsson T., Warren G. The TGN38 glycoprotein contains two non-overlapping signals that mediate localization to the trans-Golgi network. J Cell Biol. 1994 Apr;125(2):253–268. doi: 10.1083/jcb.125.2.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Rambourg A., Clermont Y. Three-dimensional electron microscopy: structure of the Golgi apparatus. Eur J Cell Biol. 1990 Apr;51(2):189–200. [PubMed] [Google Scholar]
  57. Reaves B., Banting G. Perturbation of the morphology of the trans-Golgi network following Brefeldin A treatment: redistribution of a TGN-specific integral membrane protein, TGN38. J Cell Biol. 1992 Jan;116(1):85–94. doi: 10.1083/jcb.116.1.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Redding K., Holcomb C., Fuller R. S. Immunolocalization of Kex2 protease identifies a putative late Golgi compartment in the yeast Saccharomyces cerevisiae. J Cell Biol. 1991 May;113(3):527–538. doi: 10.1083/jcb.113.3.527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Rehemtulla A., Dorner A. J., Kaufman R. J. Regulation of PACE propeptide-processing activity: requirement for a post-endoplasmic reticulum compartment and autoproteolytic activation. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8235–8239. doi: 10.1073/pnas.89.17.8235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Roberts P. C., Garten W., Klenk H. D. Role of conserved glycosylation sites in maturation and transport of influenza A virus hemagglutinin. J Virol. 1993 Jun;67(6):3048–3060. doi: 10.1128/jvi.67.6.3048-3060.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Robertson B. J., Moehring J. M., Moehring T. J. Defective processing of the insulin receptor in an endoprotease-deficient Chinese hamster cell strain is corrected by expression of mouse furin. J Biol Chem. 1993 Nov 15;268(32):24274–24277. [PubMed] [Google Scholar]
  62. Roebroek A. J., Creemers J. W., Pauli I. G., Kurzik-Dumke U., Rentrop M., Gateff E. A., Leunissen J. A., Van de Ven W. J. Cloning and functional expression of Dfurin2, a subtilisin-like proprotein processing enzyme of Drosophila melanogaster with multiple repeats of a cysteine motif. J Biol Chem. 1992 Aug 25;267(24):17208–17215. [PubMed] [Google Scholar]
  63. Rothman J. E. Protein sorting by selective retention in the endoplasmic reticulum and Golgi stack. Cell. 1987 Aug 14;50(4):521–522. doi: 10.1016/0092-8674(87)90024-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Schulze-Garg C., Böker C., Nadimpalli S. K., von Figura K., Hille-Rehfeld A. Tail-specific antibodies that block return of 46,000 M(r) mannose 6-phosphate receptor to the trans-Golgi network. J Cell Biol. 1993 Aug;122(3):541–551. doi: 10.1083/jcb.122.3.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Seidah N. G., Day R., Marcinkiewicz M., Benjannet S., Chrétien M. Mammalian neural and endocrine pro-protein and pro-hormone convertases belonging to the subtilisin family of serine proteinases. Enzyme. 1991;45(5-6):271–284. doi: 10.1159/000468901. [DOI] [PubMed] [Google Scholar]
  66. Sossin W. S., Fisher J. M., Scheller R. H. Sorting within the regulated secretory pathway occurs in the trans-Golgi network. J Cell Biol. 1990 Jan;110(1):1–12. doi: 10.1083/jcb.110.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Steiner D. F., Smeekens S. P., Ohagi S., Chan S. J. The new enzymology of precursor processing endoproteases. J Biol Chem. 1992 Nov 25;267(33):23435–23438. [PubMed] [Google Scholar]
  68. Stieneke-Gröber A., Vey M., Angliker H., Shaw E., Thomas G., Roberts C., Klenk H. D., Garten W. Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J. 1992 Jul;11(7):2407–2414. doi: 10.1002/j.1460-2075.1992.tb05305.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Teasdale R. D., D'Agostaro G., Gleeson P. A. The signal for Golgi retention of bovine beta 1,4-galactosyltransferase is in the transmembrane domain. J Biol Chem. 1992 Feb 25;267(6):4084–4096. [PubMed] [Google Scholar]
  70. Tooze J., Hollinshead M. In AtT20 and HeLa cells brefeldin A induces the fusion of tubular endosomes and changes their distribution and some of their endocytic properties. J Cell Biol. 1992 Aug;118(4):813–830. doi: 10.1083/jcb.118.4.813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Trowbridge I. S., Collawn J. F., Hopkins C. R. Signal-dependent membrane protein trafficking in the endocytic pathway. Annu Rev Cell Biol. 1993;9:129–161. doi: 10.1146/annurev.cb.09.110193.001021. [DOI] [PubMed] [Google Scholar]
  72. 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 Dec 15;268(35):26461–26465. [PubMed] [Google Scholar]
  73. Vey M., Orlich M., Adler S., Klenk H. D., Rott R., Garten W. Hemagglutinin activation of pathogenic avian influenza viruses of serotype H7 requires the protease recognition motif R-X-K/R-R. Virology. 1992 May;188(1):408–413. doi: 10.1016/0042-6822(92)90775-K. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Vey M., Schäfer W., Berghöfer S., Klenk H. D., Garten W. Maturation of the trans-Golgi network protease furin: compartmentalization of propeptide removal, substrate cleavage, and COOH-terminal truncation. J Cell Biol. 1994 Dec;127(6 Pt 2):1829–1842. doi: 10.1083/jcb.127.6.1829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Vey M., Schäfer W., Reis B., Ohuchi R., Britt W., Garten W., Klenk H. D., Radsak K. Proteolytic processing of human cytomegalovirus glycoprotein B (gpUL55) is mediated by the human endoprotease furin. Virology. 1995 Jan 10;206(1):746–749. doi: 10.1016/s0042-6822(95)80002-6. [DOI] [PubMed] [Google Scholar]
  76. Vidricaire G., Denault J. B., Leduc R. Characterization of a secreted form of human furin endoprotease. Biochem Biophys Res Commun. 1993 Sep 15;195(2):1011–1018. doi: 10.1006/bbrc.1993.2145. [DOI] [PubMed] [Google Scholar]
  77. Walker J. A., Molloy S. S., Thomas G., Sakaguchi T., Yoshida T., Chambers T. M., Kawaoka Y. Sequence specificity of furin, a proprotein-processing endoprotease, for the hemagglutinin of a virulent avian influenza virus. J Virol. 1994 Feb;68(2):1213–1218. doi: 10.1128/jvi.68.2.1213-1218.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Watanabe T., Murakami K., Nakayama K. Positional and additive effects of basic amino acids on processing of precursor proteins within the constitutive secretory pathway. FEBS Lett. 1993 Apr 12;320(3):215–218. doi: 10.1016/0014-5793(93)80589-m. [DOI] [PubMed] [Google Scholar]
  79. Weisz O. A., Swift A. M., Machamer C. E. Oligomerization of a membrane protein correlates with its retention in the Golgi complex. J Cell Biol. 1993 Sep;122(6):1185–1196. doi: 10.1083/jcb.122.6.1185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Wilcox C. A., Redding K., Wright R., Fuller R. S. Mutation of a tyrosine localization signal in the cytosolic tail of yeast Kex2 protease disrupts Golgi retention and results in default transport to the vacuole. Mol Biol Cell. 1992 Dec;3(12):1353–1371. doi: 10.1091/mbc.3.12.1353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Wise R. J., Barr P. J., Wong P. A., Kiefer M. C., Brake A. J., Kaufman R. J. 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. 1990 Dec;87(23):9378–9382. doi: 10.1073/pnas.87.23.9378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Wong S. H., Hong W. The SXYQRL sequence in the cytoplasmic domain of TGN38 plays a major role in trans-Golgi network localization. J Biol Chem. 1993 Oct 25;268(30):22853–22862. [PubMed] [Google Scholar]
  83. Wong S. H., Low S. H., Hong W. The 17-residue transmembrane domain of beta-galactoside alpha 2,6-sialyltransferase is sufficient for Golgi retention. J Cell Biol. 1992 Apr;117(2):245–258. doi: 10.1083/jcb.117.2.245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. de Curtis I., Simons K. Dissection of Semliki Forest virus glycoprotein delivery from the trans-Golgi network to the cell surface in permeabilized BHK cells. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8052–8056. doi: 10.1073/pnas.85.21.8052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. van de Ven W. J., Voorberg J., Fontijn R., Pannekoek H., van den Ouweland A. M., van Duijnhoven H. L., Roebroek A. J., Siezen R. J. Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Mol Biol Rep. 1990 Nov;14(4):265–275. doi: 10.1007/BF00429896. [DOI] [PubMed] [Google Scholar]

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