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Furin  -  furin (paired basic amino acid cleaving...

Mus musculus

Synonyms: 9130404I01Rik, Dibasic-processing enzyme, Fur, PACE, Paired basic amino acid residue-cleaving enzyme, ...
 
 
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Disease relevance of Furin

 

Psychiatry related information on Furin

  • Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia [5].
 

High impact information on Furin

 

Chemical compound and disease context of Furin

  • Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection [10].
  • In both S. typhimurium and E. coli, mntH:lacZ constructs were strongly induced by hydrogen peroxide, weakly induced by EDTA and unresponsive to paraquat, consistent with the presence of Fur and OxyR binding sites in the promoters [11].
  • The E2 glycoprotein of Sindbis virus is synthesized as a precursor, PE2, which is cleaved by furin or a furin-like host cell protease at a late stage of maturation [12].
  • One potential target for IalphaIp is furin, a cell-associated serine endopeptidase essential for the activation of protective antigen and the formation of anthrax lethal toxin (LT) [13].
  • Protection from anthrax toxin-mediated killing of macrophages by the combined effects of furin inhibitors and chloroquine [14].
 

Biological context of Furin

  • Embryos lacking Furin die between days 10.5 and 11.5, presumably due to hemodynamic insufficiency associated with severe ventral closure defects and the failure of the heart tube to fuse and undergo looping morphogenesis [15].
  • Furin is a mammalian endoprotease that cleaves proproteins at a consensus sequence of basic amino acids found in the insulin proreceptor [16].
  • The gene for Furin was assigned to the mouse chromosome 7D1-7E2 region [17].
  • Thus, although furin and PACE4 mRNA (4.4 kb each) exhibit a widespread tissue distribution only furin is ubiquitously expressed [18].
  • The PC3 gene consists of 14 exons spanning more than 35 kb [19].
 

Anatomical context of Furin

  • Furin catalyzes the proteolytic maturation of many proproteins within the trans-Golgi network (TGN)/endosomal system [20].
  • Because the ExE itself produces the proteases Furin and PACE4 to activate Nodal, it represents the first example, to our knowledge, of a stem cell compartment that actively maintains its own microenvironment [21].
  • Using a chimera approach, we show that Furin activity is required in epiblast derivatives, including the primitive heart, gut and extraembryonic mesoderm, whereas it is nonessential in the visceral endoderm [22].
  • Overall, we conclude that Furin activity is essential in both extraembryonic and precardiac mesoderm, and in definitive endoderm derivatives [22].
  • Thus, chimeric embryos, derived by injecting wild-type embryonic stem (ES) cells into fur(-/-) blastocysts, develop normally until at least 9.5 d.p.c. In contrast, Furin-deficient chimeras developing in the context of wild-type visceral endoderm fail to undergo ventral closure, axial rotation and yolk sac vascularization [22].
 

Associations of Furin with chemical compounds

  • Furin, the mammalian prototype of a family of serine proteases, is required for ventral closure and axial rotation, and formation of the yolk sac vasculature [22].
  • PC5 mRNA (3.8 kb major) is more restricted in its distribution than PACE4 and furin, and it exhibits the presence of multiple mRNA forms, resulting in variable lengths of the C-terminal Cys-rich domain [18].
  • The furin-expressing MIN6 cells exhibited less insulin content and weakened insulin secretion in response to a high glucose concentration [23].
  • COS-7 and PC12 cells expressed only furin, secreted constitutively, and processed PSS preferentially at monobasic sites to SS-28 (40-43%) and antrin (27-29%) [24].
  • Kainic acid increases the expression of the prohormone convertases furin and PC1 in the mouse hippocampus [25].
 

Regulatory relationships of Furin

  • The conditioned medium from furin-expressing MIN6 cells also exerted a decrease of PC2 and PC3 expression in unaltered MIN6 cells [23].
  • Furin-positive parietal cells expressed a high level of epidermal growth factor receptor (EGFR) [26].
  • These results indicate that the basic pair and the RXK/RR sequence are the signals for precursor cleavages catalyzed by PC3 within the regulated secretory pathway and by furin within the constitutive pathway, respectively [27].
  • This reveals the presence of the proprotein convertase-MT1-MMP axis in flow-induced arterial remodeling and identifies furin as a possible target for local intervention in pathological arterial remodeling [28].
  • TGF-alpha stimulated the furin promoter activity highly in a mouse GSM cell line GSM06 [26].
 

Other interactions of Furin

  • 2) Both PC1/3 and PC5/6A also processed the N-terminal site but less efficiently than furin [29].
  • 4) The Q10R mutant was significantly more susceptible to furin cleavage at the N-terminal site than the wild-type pro-GHRH [29].
  • An ArgGlyAsp tripeptide identical to the recognition sequence of integrins was observed in the structures of the mammalian PC1, PC2, and Furin [30].
  • Furin transcript was detected in both germ and somatic cells, while PC4 transcript was found only in round spermatids [31].
  • Here we show additionally that left-sided expression of pitx2 and lefty-2 are also perturbed in Furin-deficient embryos [22].
 

Analytical, diagnostic and therapeutic context of Furin

  • The chromosomal localization of the genes coding for the pro-protein and pro-hormone convertases PC1, PC2, and Furin has been achieved by in situ hybridization [17].
  • Immunocytochemistry detects furin immunoreactivity in pro-acinar and ductal cells of glands from newborn and pubescent mice [32].
  • Northern blot analysis revealed that PC6 mRNA, as with furin and PACE4 mRNAs, was expressed in various tissues and cell lines, with the highest level in the intestine [33].
  • Despite the presence of a potential furin cleavage site and in contrast to LRP1, immunoblotting for LRP1b reveals the presence of a single 600-kDa polypeptide species [34].
  • In order to investigate the cleavage of proSAAS by prohormone convertases, we incubated recombinant His-tagged proSAAS with recombinant mouse proPC2 or furin, separated the cleavage products using high-pressure gel permeation chromatography and analyzed the products by RIA [35].

References

  1. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Henrich, S., Cameron, A., Bourenkov, G.P., Kiefersauer, R., Huber, R., Lindberg, I., Bode, W., Than, M.E. Nat. Struct. Biol. (2003) [Pubmed]
  2. Furin-mediated cleavage of Pseudomonas exotoxin-derived chimeric toxins. Chiron, M.F., Fryling, C.M., FitzGerald, D. J. Biol. Chem. (1997) [Pubmed]
  3. Furin is important but not essential for the proteolytic maturation of gp160 of HIV-1. Gu, M., Rappaport, J., Leppla, S.H. FEBS Lett. (1995) [Pubmed]
  4. Resuscitating mutations in a furin cleavage-deficient mutant of the flavivirus tick-borne encephalitis virus. Elshuber, S., Mandl, C.W. J. Virol. (2005) [Pubmed]
  5. Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia. Kim, S.H., Wang, R., Gordon, D.J., Bass, J., Steiner, D.F., Lynn, D.G., Thinakaran, G., Meredith, S.C., Sisodia, S.S. Nat. Neurosci. (1999) [Pubmed]
  6. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Thomas, G. Nat. Rev. Mol. Cell Biol. (2002) [Pubmed]
  7. SPC4/PACE4 regulates a TGFbeta signaling network during axis formation. Constam, D.B., Robertson, E.J. Genes Dev. (2000) [Pubmed]
  8. Major histocompatibility complex class I viral antigen processing in the secretory pathway defined by the trans-Golgi network protease furin. Gil-Torregrosa, B.C., Raúl Castaño, A., Del Val, M. J. Exp. Med. (1998) [Pubmed]
  9. Proteolytic processing activates a viral superantigen. Mix, D., Winslow, G.M. J. Exp. Med. (1996) [Pubmed]
  10. Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection. Kibler, K.V., Miyazato, A., Yedavalli, V.S., Dayton, A.I., Jacobs, B.L., Dapolito, G., Kim, S.J., Jeang, K.T. J. Biol. Chem. (2004) [Pubmed]
  11. The NRAMP proteins of Salmonella typhimurium and Escherichia coli are selective manganese transporters involved in the response to reactive oxygen. Kehres, D.G., Zaharik, M.L., Finlay, B.B., Maguire, M.E. Mol. Microbiol. (2000) [Pubmed]
  12. The amino-terminal residue of Sindbis virus glycoprotein E2 influences virus maturation, specific infectivity for BHK cells, and virulence in mice. Heidner, H.W., Johnston, R.E. J. Virol. (1994) [Pubmed]
  13. Inter-alpha-inhibitor proteins are endogenous furin inhibitors and provide protection against experimental anthrax intoxication. Opal, S.M., Artenstein, A.W., Cristofaro, P.A., Jhung, J.W., Palardy, J.E., Parejo, N.A., Lim, Y.P. Infect. Immun. (2005) [Pubmed]
  14. Protection from anthrax toxin-mediated killing of macrophages by the combined effects of furin inhibitors and chloroquine. Komiyama, T., Swanson, J.A., Fuller, R.S. Antimicrob. Agents Chemother. (2005) [Pubmed]
  15. Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin. Roebroek, A.J., Umans, L., Pauli, I.G., Robertson, E.J., van Leuven, F., Van de Ven, W.J., Constam, D.B. Development (1998) [Pubmed]
  16. Defective processing of the insulin receptor in an endoprotease-deficient Chinese hamster cell strain is corrected by expression of mouse furin. Robertson, B.J., Moehring, J.M., Moehring, T.J. J. Biol. Chem. (1993) [Pubmed]
  17. Chromosomal assignments of the genes for neuroendocrine convertase PC1 (NEC1) to human 5q15-21, neuroendocrine convertase PC2 (NEC2) to human 20p11.1-11.2, and furin (mouse 7[D1-E2] region). Seidah, N.G., Mattei, M.G., Gaspar, L., Benjannet, S., Mbikay, M., Chrétien, M. Genomics (1991) [Pubmed]
  18. The family of subtilisin/kexin like pro-protein and pro-hormone convertases: divergent or shared functions. Seidah, N.G., Chrétien, M., Day, R. Biochimie (1994) [Pubmed]
  19. Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Ohagi, S., Sakaguchi, H., Sanke, T., Tatsuta, H., Hanabusa, T., Nanjo, K. Diabetes (1996) [Pubmed]
  20. Cytoskeletal protein ABP-280 directs the intracellular trafficking of furin and modulates proprotein processing in the endocytic pathway. Liu, G., Thomas, L., Warren, R.A., Enns, C.A., Cunningham, C.C., Hartwig, J.H., Thomas, G. J. Cell Biol. (1997) [Pubmed]
  21. Nodal protein processing and fibroblast growth factor 4 synergize to maintain a trophoblast stem cell microenvironment. Guzman-Ayala, M., Ben-Haim, N., Beck, S., Constam, D.B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  22. Tissue-specific requirements for the proprotein convertase furin/SPC1 during embryonic turning and heart looping. Constam, D.B., Robertson, E.J. Development (2000) [Pubmed]
  23. Proprotein-processing endoprotease furin decreases regulated secretory pathway-specific proteins in the pancreatic beta cell line MIN6. Kayo, T., Sawada, Y., Suzuki, Y., Suda, M., Tanaka, S., Konda, Y., Miyazaki, J., Takeuchi, T. J. Biol. Chem. (1996) [Pubmed]
  24. Heterologous processing of prosomatostatin in constitutive and regulated secretory pathways. Putative role of the endoproteases furin, PC1, and PC2. Galanopoulou, A.S., Kent, G., Rabbani, S.N., Seidah, N.G., Patel, Y.C. J. Biol. Chem. (1993) [Pubmed]
  25. Kainic acid increases the expression of the prohormone convertases furin and PC1 in the mouse hippocampus. Meyer, A., Chrétien, P., Massicotte, G., Sargent, C., Chrétien, M., Marcinkiewicz, M. Brain Res. (1996) [Pubmed]
  26. Kex2 family endoprotease furin is expressed specifically in pit-region parietal cells of the rat gastric mucosa. Kamimura, H., Konda, Y., Yokota, H., Takenoshita, S., Nagamachi, Y., Kuwano, H., Takeuchi, T. Am. J. Physiol. (1999) [Pubmed]
  27. Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway. Hosaka, M., Nagahama, M., Kim, W.S., Watanabe, T., Hatsuzawa, K., Ikemizu, J., Murakami, K., Nakayama, K. J. Biol. Chem. (1991) [Pubmed]
  28. Furin and membrane type-1 metalloproteinase mRNA levels and activation of metalloproteinase-2 are associated with arterial remodeling. de Kleijn, D.P., Sluijter, J.P., Smit, J., Velema, E., Richard, W., Schoneveld, A.H., Pasterkamp, G., Borst, C. FEBS Lett. (2001) [Pubmed]
  29. Furin and prohormone convertase 1/3 are major convertases in the processing of mouse pro-growth hormone-releasing hormone. Dey, A., Norrbom, C., Zhu, X., Stein, J., Zhang, C., Ueda, K., Steiner, D.F. Endocrinology (2004) [Pubmed]
  30. Cloning and primary sequence of a mouse candidate prohormone convertase PC1 homologous to PC2, Furin, and Kex2: distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Seidah, N.G., Marcinkiewicz, M., Benjannet, S., Gaspar, L., Beaubien, G., Mattei, M.G., Lazure, C., Mbikay, M., Chrétien, M. Mol. Endocrinol. (1991) [Pubmed]
  31. Localization of Kex2-like processing endoproteases, furin and PC4, within mouse testis by in situ hybridization. Torii, S., Yamagishi, T., Murakami, K., Nakayama, K. FEBS Lett. (1993) [Pubmed]
  32. Prohormone convertases in mouse submandibular gland: co-localization of furin and nerve growth factor. Farhadi, H., Pareek, S., Day, R., Dong, W., Chrétien, M., Bergeron, J.J., Seidah, N.G., Murphy, R.A. J. Histochem. Cytochem. (1997) [Pubmed]
  33. Identification and functional expression of a new member of the mammalian Kex2-like processing endoprotease family: its striking structural similarity to PACE4. Nakagawa, T., Hosaka, M., Torii, S., Watanabe, T., Murakami, K., Nakayama, K. J. Biochem. (1993) [Pubmed]
  34. Normal development and fertility of knockout mice lacking the tumor suppressor gene LRP1b suggest functional compensation by LRP1. Marschang, P., Brich, J., Weeber, E.J., Sweatt, J.D., Shelton, J.M., Richardson, J.A., Hammer, R.E., Herz, J. Mol. Cell. Biol. (2004) [Pubmed]
  35. Tissue distribution and processing of proSAAS by proprotein convertases. Sayah, M., Fortenberry, Y., Cameron, A., Lindberg, I. J. Neurochem. (2001) [Pubmed]
 
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