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

• Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160 [12].
• Furin, a subtilisin-like eukaryotic endoprotease, has a substrate specificity for the consensus amino-acid sequence Arg-X-Lys/Arg-Arg at the cleavage site [12].
• We have recently found that the enzyme activating the haemagglutinin of fowl plague virus (FPV), an avian influenza virus, is furin [12].
• A human gene product, "furin," shares 50% identity with the catalytic domain of Kex2 protease and is, therefore, a candidate for a human prohormone-processing enzyme [13].
• These studies show that phosphorylation and association with Atf1 are required for nuclear localization of Spc1 [14].

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

• By coexpression of vWF and various propeptide processing enzymes in COS-1 cells, we here demonstrate that vWF is preferentially processed by the paired dibasic amino acid-cleaving enzyme PACE (furin) [23].
• After initial autocatalytic cleavage, the prosegment remains tightly associated with the convertase until it reaches the trans-Golgi network where the dissociation of the prosegment and activation of furin occurs [1].
• In contrast, the loss-of-function mutations A443T and C679X lead either to the lack of trans-Golgi network/recycling endosome localization and an enhanced susceptibility to furin cleavage (A443T) or to the inability of PCSK9 to exit the endoplasmic reticulum (C679X) [3].
• Furin-independent pathway of membrane type 1-matrix metalloproteinase activation in rabbit dermal fibroblasts [24].
• EXPERIMENTAL DESIGN: We evaluated furin and VEGF-C expression and microvessel density (MVD) by immunohistochemistry in human tongue sections harboring normal epithelium, dysplastic epithelium, and/or SCC [25].

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

• Indeed, ADAMTS4 is co-localized with furin in trans-Golgi network [35].
• PTHrP was colocalized with furin in 75% of gastric cancer tissues (six of eight) from patients with high serum PTHrP levels [36].
• Immunoelectron microscopy showed unequivocally that furin resides in the TGN where it colocalized with TGN38 [37].
• BACE and furin co-localize within the Golgi apparatus, and propeptide cleavage is inhibited by brefeldin A and monensin, drugs that disrupt trafficking through the Golgi [38].
• In FBD, furin was found to be colocalized with ABri deposits and amyloid angiopathy in all areas examined [8].

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].

References