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Gene Review

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

Homo sapiens

Synonyms: Dibasic-processing enzyme, FUR, Furin, PACE, PCSK3, ...
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Disease relevance of FURIN

  • PpFur expression in head and neck squamous cell carcinoma cell lines showed a mechanistic link between furin inhibition, decreased substrate processing, cell proliferation, and invasive ability [1].
  • Our findings unveil a new facet of the physiological consequences of hypoxia/HIF-1, through enhanced furin-induced proteolytic processing/activation of proproteins known to be involved in tumorigenesis [2].
  • The data show that the natural gain-of-function mutations R218S, F216L, and D374Y associated with hypercholesterolemia result in total or partial loss of furin/PC5/6A processing at the motif RFHR(218) downward arrow [3].
  • Furin, a member of the eukaryotic subtilisin family, has been shown to be an activating protease for HIV [4].
  • Furin- and LPC/PC7-catalyzed cleavage of HIV-1 gp160 resulted in biologically active envelope protein [4].
  • Our results demonstrate significantly decreased in situ immunoreactivity of furin in the epidermis of patients with progressive vitiligo (n = 10), suggesting H(2)O(2)-mediated oxidation [5].
  • This study demonstrated that furin overexpression in some types of hepatocellular carcinomas is TR dependent and might play a crucial role in the development of hepatocellular carcinoma [6].

Psychiatry related information on FURIN

  • Recently, the involvement of furin in diseases ranging from Alzheimer's disease and cancer to anthrax and Ebola fever has created additional focus on proprotein processing [7].
  • Familial British dementia: colocalization of furin and ABri amyloid [8].
  • Persons with developmental disabilities are susceptible to the full range of psychiatric disorders (Szymanski, Madow, Mallory, Menolascino, & Pace, 1991) [9].
  • The mean reaction time for the left hand under the Slow Pace was significantly longer than that under the Middle Pace condition (p < .05), which showed that the subjects were required to give more attention to right-hand performance at the slow pace as it was difficult [10].
  • In the current investigation, a modification was made to the preference assessment described by Pace, Ivancic, Edwards, Iwata, and Page (1985) to predict the effects of stimuli when used in a differential-reinforcement-of-other-behavior (DRO) schedule for 2 clients with severe self-injurious behavior (SIB) and profound mental retardation [11].

High impact information on FURIN


Chemical compound and disease context of FURIN

  • Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca(2+) stabilization [15].
  • In this work, we examined inhibition by purified, recombinant bacterial prosegments of furin and PC7 on the in vitro processing of either the fluorogenic peptide pERTKR-MCA or the human immunodeficiency virus envelope glycoprotein gp160 [16].
  • Here, we demonstrate the utility of the protein-based inhibitor alpha1-antitrypsin Portland (alpha1-PDX) as an antipathogenic agent that can be used prophylactically to block furin-dependent cell killing by Pseudomonas exotoxin A [17].
  • Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen [18].
  • Although many paramyxovirus F proteins are proteolytically processed by the cellular protease furin at a multibasic cleavage motif, cleavage of the newly emerged Hendra virus F protein occurs by a previously unidentified cellular protease following a single lysine at residue 109 [19].

Biological context of FURIN

  • The luminal N-terminus of sortilin comprises a consensus sequence for cleavage by furin, R41WRR44, which precedes a truncation originally found in sortilin isolated from human brain [20].
  • Missense mutations in four of the five basic residues within this sequence account for approximately 20% of all known XLHED cases, with mutations occurring most frequently at Arg156, which is shared by the two consensus furin sites [21].
  • These analyses suggest that cleavage at the furin site(s) in the stalk region is required for the EDA-mediated cell-to-cell signaling that regulates the morphogenesis of ectodermal appendages [21].
  • These findings suggest that furin inhibition is a feasible approach to ameliorate and even abolish the malignant phenotype of various malignancies [1].
  • Treatment of transfected cells with a furin inhibitor resulted in a dose-dependent inhibition of proMMP-2 cleavage; recombinant tissue inhibitor of metalloproteinase-2, which binds to the active site of membrane type 1-MMP, had no inhibitory effect [22].

Anatomical context of FURIN


Associations of FURIN with chemical compounds

  • Several substitutions in the P6-P3 sequence were well tolerated; however, replacement of the Lys at the P6 position with Gly and replacement of the P3 Lys by an acidic residue led to markedly compromised cleavage by furin [26].
  • Three different strategies were used to explore processing events in the C-terminal region: site-directed mutagenesis of the furin cleavage site, treatment with a competitive inhibitor of all furin family members, and interference with Golgi modifications by Brefeldin A [27].
  • Significant homology, especially with respect to the topography of cysteine residues, was found between the cysteine-rich regions of the human insulin receptor, the human epidermal growth factor receptor and furin [28].
  • Expression of dominant-negative PACS-1 causes a mislocalization of both furin and mannose 6-phosphate receptor from the trans-Golgi network, but has no effect on the localization of proteins that do not contain acidic cluster sorting motifs [29].
  • Finally, employing (i) furin constructs that mimic either non-phosphorylated or phosphorylated furin and (ii) the phosphatase inhibitor tautomycin, we show that the phosphorylation state of the furin cytoplasmic tail modulates retrieval of the endoprotease to the TGN [30].

Physical interactions of FURIN

  • Analysis of furin promoters revealed the presence of putative binding sites for hypoxia-inducible factor-1 (HIF-1), a transcription complex that plays a pivotal role in cellular adaptation to hypoxia [2].
  • Computer-assisted search of the furin promoter sequence revealed multiple potential binding motifs for GATA-1, suggesting that furin is expressed and regulated in these cells [31].
  • Abrogation of activation of proMT1-MMP with a furin inhibitor prevented binding and endocytosis of 125I-TIMP-2 [32].

Enzymatic interactions of FURIN

  • Furin-cleaved MMP-2 does not possess proteolytic activity as examined in a cell-free assay [22].
  • We also showed that a synthetic peptide comprising the -6 to +7 sequence of human pro-PTH is appropriately cleaved by purified furin in vitro [26].
  • Furin directly cleaves proMMP-2 in the trans-Golgi network resulting in a nonfunctioning proteinase [22].
  • Here, we report that during its transport through the Golgi apparatus, ADAM17 is included in cholesterol-rich membrane microdomains (lipid rafts) where its prodomain is cleaved by furin [33].
  • Using in vivo [(32)P]orthophosphate labeling of cells expressing transfected Notch1, we observed that the furin cleaved Notch1 (TMIC) and the soluble intracellular forms (NICD), but not the full-length molecule were phosphorylated [34].

Co-localisations of FURIN


Regulatory relationships of FURIN

  • Thus, we propose that PCSK9 levels are finely regulated by the basic amino acid convertases furin and PC5/6A [3].
  • Alternative pathway for the role of furin in tumor cell invasion process. Enhanced MMP-2 levels through bioactive TGFbeta [39].
  • BCL-2-induced glioma cell invasiveness depends on furin-like proteases [40].
  • Inhibition of furin-like PCs with the specific pharmacological inhibitor decanoyl-RVKR-chloromethylketone (dec-CMK) inhibited MT1-MMP activation in macrophages [41].
  • Furin convertase activates several precursor matrix metalloproteinases involved in the degradation of the extracellular matrix [25].
  • Mutation studies of Furin indicate that Mint3 regulates Furin distribution mainly through interaction with the acidic peptide signal of Furin [42].

Other interactions of FURIN

  • Sortilin is synthesized as a proform which, in late Golgi compartments, is converted to the mature receptor by furin-mediated cleavage of a 44 residue N-terminal propeptide [20].
  • Processing of proMT1-MMP as well as the expression of its proteolytic activity were blocked by mutating these recognition motifs or by inhibiting the proprotein convertases furin and PC6 with the serpin-based inhibitor alpha(1) antitrypsin Portland [43].
  • Here, we report that a dibasic amino acid convertase, furin, directly cleaves proMMP-2 within the trans-Golgi network leading to an inactive form of matrix metalloproteinase-2 (MMP-2) [22].
  • In both cell types, furin was the most effective in processing proPTH to PTH [44].
  • In addition, our evidence suggests that a furin-independent pathway may also contribute to the activation of ADAMTS4 [35].

Analytical, diagnostic and therapeutic context of FURIN

  • Site-directed mutagenesis of amino acids in the furin consensus recognition motif of proMMP-2(R69KPR72) prevented propeptide cleavage, thereby identifying the scissile bond and characterizing the basic amino acids required for cleavage [22].
  • Northern blot analyses revealed that furin and the recently discovered protease LPC/PC7 were the only subtilisin-like enzymes transcribed in such cells [4].
  • Sections from 46 glossectomy specimens were assessed for furin expression [25].
  • We also evaluated the pattern of furin expression and VEGF-C processing by Western blot analysis in three SCC cell lines with different degrees of aggressiveness [25].
  • Transcripts for both PC1 and furin convertase were detectable in skin-derived mast cells and HMC-1 cells, as shown by RT-PCR [45].


  1. Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. López de Cicco, R., Bassi, D.E., Zucker, S., Seidah, N.G., Klein-Szanto, A.J. Cancer Res. (2005) [Pubmed]
  2. Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. McMahon, S., Grondin, F., McDonald, P.P., Richard, D.E., Dubois, C.M. J. Biol. Chem. (2005) [Pubmed]
  3. The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and/or PC5/6A: FUNCTIONAL CONSEQUENCES OF NATURAL MUTATIONS AND POST-TRANSLATIONAL MODIFICATIONS. Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N.G. J. Biol. Chem. (2006) [Pubmed]
  4. The role of eukaryotic subtilisin-like endoproteases for the activation of human immunodeficiency virus glycoproteins in natural host cells. Hallenberger, S., Moulard, M., Sordel, M., Klenk, H.D., Garten, W. J. Virol. (1997) [Pubmed]
  5. The Ca2+-binding capacity of epidermal furin is disrupted by H2O2-mediated oxidation in vitiligo. Spencer, J.D., Gibbons, N.C., Böhm, M., Schallreuter, K.U. Endocrinology (2008) [Pubmed]
  6. Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines. Chen, R.N., Huang, Y.H., Lin, Y.C., Yeh, C.T., Liang, Y., Chen, S.L., Lin, K.H. Endocrinology (2008) [Pubmed]
  7. Prediction of proprotein convertase cleavage sites. Duckert, P., Brunak, S., Blom, N. Protein Eng. Des. Sel. (2004) [Pubmed]
  8. Familial British dementia: colocalization of furin and ABri amyloid. Schwab, C., Hosokawa, M., Akiyama, H., McGeer, P.L. Acta Neuropathol. (2003) [Pubmed]
  9. Posttraumatic stress disorder in persons with developmental disabilities. Ryan, R. Community mental health journal. (1994) [Pubmed]
  10. Effect of slow movement execution on cognitive function. Naruse, K., Sakuma, H., Hirai, T. Perceptual and motor skills. (2004) [Pubmed]
  11. A preliminary procedure for predicting the positive and negative effects of reinforcement-based procedures. Piazza, C.C., Fisher, W.W., Hanley, G.P., Hilker, K., Derby, K.M. Journal of applied behavior analysis. (1996) [Pubmed]
  12. Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Hallenberger, S., Bosch, V., Angliker, H., Shaw, E., Klenk, H.D., Garten, W. Nature (1992) [Pubmed]
  13. Intracellular targeting and structural conservation of a prohormone-processing endoprotease. Fuller, R.S., Brake, A.J., Thorner, J. Science (1989) [Pubmed]
  14. Phosphorylation and association with the transcription factor Atf1 regulate localization of Spc1/Sty1 stress-activated kinase in fission yeast. Gaits, F., Degols, G., Shiozaki, K., Russell, P. Genes Dev. (1998) [Pubmed]
  15. Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca(2+) stabilization. Chen, C.D., Huff, M.E., Matteson, J., Page, L., Phillips, R., Kelly, J.W., Balch, W.E. EMBO J. (2001) [Pubmed]
  16. The prosegments of furin and PC7 as potent inhibitors of proprotein convertases. In vitro and ex vivo assessment of their efficacy and selectivity. Zhong, M., Munzer, J.S., Basak, A., Benjannet, S., Mowla, S.J., Decroly, E., Chrétien, M., Seidah, N.G. J. Biol. Chem. (1999) [Pubmed]
  17. alpha1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Jean, F., Stella, K., Thomas, L., Liu, G., Xiang, Y., Reason, A.J., Thomas, G. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  18. Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen. Molloy, S.S., Bresnahan, P.A., Leppla, S.H., Klimpel, K.R., Thomas, G. J. Biol. Chem. (1992) [Pubmed]
  19. Cathepsin L is involved in proteolytic processing of the Hendra virus fusion protein. Pager, C.T., Dutch, R.E. J. Virol. (2005) [Pubmed]
  20. Propeptide cleavage conditions sortilin/neurotensin receptor-3 for ligand binding. Munck Petersen, C., Nielsen, M.S., Jacobsen, C., Tauris, J., Jacobsen, L., Gliemann, J., Moestrup, S.K., Madsen, P. EMBO J. (1999) [Pubmed]
  21. Mutations within a furin consensus sequence block proteolytic release of ectodysplasin-A and cause X-linked hypohidrotic ectodermal dysplasia. Chen, Y., Molloy, S.S., Thomas, L., Gambee, J., Bächinger, H.P., Ferguson, B., Zonana, J., Thomas, G., Morris, N.P. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  22. Furin directly cleaves proMMP-2 in the trans-Golgi network resulting in a nonfunctioning proteinase. Cao, J., Rehemtulla, A., Pavlaki, M., Kozarekar, P., Chiarelli, C. J. Biol. Chem. (2005) [Pubmed]
  23. Preferred sequence requirements for cleavage of pro-von Willebrand factor by propeptide-processing enzymes. Rehemtulla, A., Kaufman, R.J. Blood (1992) [Pubmed]
  24. Furin-independent pathway of membrane type 1-matrix metalloproteinase activation in rabbit dermal fibroblasts. Sato, T., Kondo, T., Fujisawa, T., Seiki, M., Ito, A. J. Biol. Chem. (1999) [Pubmed]
  25. Simultaneous expression of furin and vascular endothelial growth factor in human oral tongue squamous cell carcinoma progression. López de Cicco, R., Watson, J.C., Bassi, D.E., Litwin, S., Klein-Szanto, A.J. Clin. Cancer Res. (2004) [Pubmed]
  26. In vitro cleavage of internally quenched fluorogenic human proparathyroid hormone and proparathyroid-related peptide substrates by furin. Generation of a potent inhibitor. Lazure, C., Gauthier, D., Jean, F., Boudreault, A., Seidah, N.G., Bennett, H.P., Hendy, G.N. J. Biol. Chem. (1998) [Pubmed]
  27. Proteolytic processing of human zona pellucida proteins. Kiefer, S.M., Saling, P. Biol. Reprod. (2002) [Pubmed]
  28. Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein. Roebroek, A.J., Schalken, J.A., Leunissen, J.A., Onnekink, C., Bloemers, H.P., Van de Ven, W.J. EMBO J. (1986) [Pubmed]
  29. PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic. Crump, C.M., Xiang, Y., Thomas, L., Gu, F., Austin, C., Tooze, S.A., Thomas, G. EMBO J. (2001) [Pubmed]
  30. Intracellular trafficking of furin is modulated by the phosphorylation state of a casein kinase II site in its cytoplasmic tail. Jones, B.G., Thomas, L., Molloy, S.S., Thulin, C.D., Fry, M.D., Walsh, K.A., Thomas, G. EMBO J. (1995) [Pubmed]
  31. Furin gene (fur) regulation in differentiating human megakaryoblastic Dami cells: involvement of the proximal GATA recognition motif in the P1 promoter and impact on the maturation of furin substrates. Laprise, M.H., Grondin, F., Cayer, P., McDonald, P.P., Dubois, C.M. Blood (2002) [Pubmed]
  32. TIMP-2 is released as an intact molecule following binding to MT1-MMP on the cell surface. Zucker, S., Hymowitz, M., Conner, C., DeClerck, Y., Cao, J. Exp. Cell Res. (2004) [Pubmed]
  33. The shedding activity of ADAM17 is sequestered in lipid rafts. Tellier, E., Canault, M., Rebsomen, L., Bonardo, B., Juhan-Vague, I., Nalbone, G., Peiretti, F. Exp. Cell Res. (2006) [Pubmed]
  34. Hyperphosphorylation and association with RBP of the intracellular domain of Notch1. Foltz, D.R., Nye, J.S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  35. Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network. Wang, P., Tortorella, M., England, K., Malfait, A.M., Thomas, G., Arner, E.C., Pei, D. J. Biol. Chem. (2004) [Pubmed]
  36. Prohormone convertase furin has a role in gastric cancer cell proliferation with parathyroid hormone-related peptide in a reciprocal manner. Nakajima, T., Konda, Y., Kanai, M., Izumi, Y., Kanda, N., Nanakin, A., Kitazawa, S., Chiba, T. Dig. Dis. Sci. (2002) [Pubmed]
  37. Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface. Molloy, S.S., Thomas, L., VanSlyke, J.K., Stenberg, P.E., Thomas, G. EMBO J. (1994) [Pubmed]
  38. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta -secretase. Bennett, B.D., Denis, P., Haniu, M., Teplow, D.B., Kahn, S., Louis, J.C., Citron, M., Vassar, R. J. Biol. Chem. (2000) [Pubmed]
  39. Alternative pathway for the role of furin in tumor cell invasion process. Enhanced MMP-2 levels through bioactive TGFbeta. McMahon, S., Laprise, M.H., Dubois, C.M. Exp. Cell Res. (2003) [Pubmed]
  40. BCL-2-induced glioma cell invasiveness depends on furin-like proteases. Wick, W., Wild-Bode, C., Frank, B., Weller, M. J. Neurochem. (2004) [Pubmed]
  41. Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis. Stawowy, P., Meyborg, H., Stibenz, D., Borges Pereira Stawowy, N., Roser, M., Thanabalasingam, U., Veinot, J.P., Chrétien, M., Seidah, N.G., Fleck, E., Graf, K. Circulation (2005) [Pubmed]
  42. Interaction of Mint3 with Furin regulates the localization of Furin in the trans-Golgi network. Han, J., Wang, Y., Wang, S., Chi, C. J. Cell. Sci. (2008) [Pubmed]
  43. Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases. Yana, I., Weiss, S.J. Mol. Biol. Cell (2000) [Pubmed]
  44. Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study. Hendy, G.N., Bennett, H.P., Gibbs, B.F., Lazure, C., Day, R., Seidah, N.G. J. Biol. Chem. (1995) [Pubmed]
  45. Human mast cells in the neurohormonal network: expression of POMC, detection of precursor proteases, and evidence for IgE-dependent secretion of alpha-MSH. Artuc, M., Böhm, M., Grützkau, A., Smorodchenko, A., Zuberbier, T., Luger, T., Henz, B.M. J. Invest. Dermatol. (2006) [Pubmed]
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