Disease relevance of Furin

• Furin, the best-characterized member of the mammalian PC family, has essential functions in embryogenesis and homeostasis but is also implicated in various pathologies such as tumor metastasis, neurodegeneration and various bacterial and viral diseases caused by such pathogens as anthrax and pathogenic Ebola virus strains [1].
• Furin-mediated cleavage of Pseudomonas exotoxin-derived chimeric toxins [2].
• Furin is important but not essential for the proteolytic maturation of gp160 of HIV-1 [3].
• A mutant of tick-borne encephalitis virus (TBEV) carrying a deletion mutation within the furin recognition motif of protein prM (changing R-T-R-R to R-T-R) was previously shown to be noninfectious in BHK-21 cells [4].
• Resuscitating mutations in a furin cleavage-deficient mutant of the flavivirus tick-borne encephalitis virus [4].

Psychiatry related information on Furin

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

High impact information on Furin

• Furin at the cutting edge: from protein traffic to embryogenesis and disease [6].
• Endoproteolytic maturation of these proteins is probably mediated by the proprotein convertase SPC1/Furin [7].
• Antigen presentation is independent of proteasome activity, but inhibitors of the trans-Golgi network resident protease furin inhibit both HBe maturation and antigen presentation [8].
• These results define a new antigen processing pathway located in the secretory route, with a central role for proteolytic maturation mediated by the subtilisin protease family member furin as an efficient source for antigen presentation [8].
• Transient transfection of the furin-negative cells with an expression plasmid containing the furin gene restored the ability to present vSAg7 efficiently [9].

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