FURIN

General Information

Full gene name:furin (paired basic amino acid cleaving enzyme) Entrez Gene ID:5045 Location:15q26.1 Synonyms:PACE, FUR, SPC1, PCSK3 Type:protein-coding

User SNPs

SNPs given by the user that are near or inside this gene:

SNP	Distance (bp)	Direction
rs8042680	94650	downstream

NCBI Summary

The protein encoded by this gene belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can efficiently cleave precursor proteins at their paired basic amino acid processing sites. Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. It is also thought to be one of the proteases responsible for the activation of HIV envelope glycoproteins gp160 and gp140. This gene is thought to play a role in tumor progression. The use of alternate polyadenylation sites has been found for this gene. [provided by RefSeq, Jul 2008]

OMIM

OMIM ID:`OMIM ID 136950 `_

NCBI Phenotypes

• Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
• NHGRI GWA Catalog

Gene Ontology

• endopeptidase activity
• protein processing
• trans-Golgi network transport vesicle
• Golgi lumen
• negative regulation of nerve growth factor production
• cell surface
• proteolysis
• transforming growth factor beta receptor signaling pathway
• plasma membrane
• signal peptide processing
• serine-type endopeptidase activity
• protease binding
• peptidase activity
• nerve growth factor receptor signaling pathway
• metal ion binding
• trans-Golgi network
• viral assembly, maturation, egress, and release
• endoplasmic reticulum membrane
• peptide binding
• cellular protein metabolic process
• extracellular matrix organization
• secretion by cell
• aging
• negative regulation of low-density lipoprotein particle receptor catabolic process
• peptide hormone processing
• nerve growth factor processing
• Golgi cisterna
• regulation of protein catabolic process
• nerve growth factor production
• extracellular space
• Notch signaling pathway
• membrane raft
• extracellular matrix disassembly
• positive regulation of transforming growth factor beta receptor signaling pathway
• nerve growth factor binding
• positive regulation of cell migration
• regulation of endopeptidase activity
• Golgi membrane
• cell proliferation
• negative regulation of transforming growth factor beta1 production
• integral to membrane
• peptidyl-glutamic acid carboxylation
• peptide biosynthetic process
• positive regulation of membrane protein ectodomain proteolysis
• serine-type endopeptidase inhibitor activity
• post-translational protein modification

KEGG Pathways

• Influenza A

GeneRIFs

• HIV-1 gp160 processing by furin is inhibited by polyarginine [PMID 15371436]
• ppFurin expression in breast cancer cells decreased MMP-9 activity, but had no significant effect on TIMP-1 secretion. [PMID 17909005]
• Kinesin adapter JLP links PIKfyve to microtubule-based endosome-to-trans-Golgi network traffic of furin. [PMID 19056739]
• furin has a role in processing human pro-CNP [PMID 12736257]
• FURIN and its substrate cytokines BAFF and APRIL are over expressed in atherosclerotic plaques. [PMID 21889147]
• we investigated the specificity and potency of complete prodomains and short C-terminal prodomain peptides of each SPC on highly purified, soluble enzyme preparations of human SPC1, SPC6, and SPC7. [PMID 11723118]
• Analysis of furin promoters revealed the presence of putative binding sites for HIF-1; hypoxic/HIF-1 regulation of furin correlated with increased proteolytic activation of substrates MMP1 and TFGbeta1. [PMID 15611046]
• Data suggest that mutations that diminish domain 2 Ca(2+) binding allow furin access to an otherwise protected cleavage site, initiating the proteolytic cascade that leads to gelsolin amyloidogenesis and familial amyloidosis of Finnish type. [PMID 14596804]
• HGF and BCL-2 family proteins use a furin-dependent pathway to promote invasion via TGF-beta and MMP in human malignant glioma cells and the pro-invasive properties of TGF-beta require furin- dependent MMP activity. [PMID 15584904]
• Increased activity of this enzyme enhances the malignant phenotype of human head and neck cancer cells. [PMID 12547702]
• releases Feline foamy virus (FFV) Env leader protein (Elp)from ENV precursor protein. [PMID 15564468]
• Proteomic profiling of CHO cells with enhanced rhBMP2 productivity following co-expression of furin is reported. [PMID 18546152]
• miR-24 might play an important role in modulating the induction of TGFbeta1 mediated by cyclical mechanical stress through direct targeting of FURIN. [PMID 20945401]
• The study reveals genotypic differences in HBeAg processing and implicates furin as the major enzyme involved in the cleavage of the first and second RXXR motifs. [PMID 19193799]
• (108)RRKR(111)/Y(112) cleavage by furin completes the removal and the degradation of the autoinhibitory prodomain and the liberation of the functional activity of the emerging enzyme of MT1-MMP. [PMID 20605791]
• furin enhances alpha-secretase activity via the cleavage of ADAM10 and TACE, and attenuated furin activity is connected to the production of Abeta [PMID 16942750]
• furin is a novel chemokine-modifying enzyme in vitro and most probably also in vivo, generating a C-terminally truncated CXCL10, which fully retains its (inverse) agonistic properties. [PMID 14739277]
• the hepatic prohormone convertase furin mediates the posttranslational processing of hepcidin. The proteolytic cleavage of prohepcidin to hepcidin is not regulated by iron-transferrin or the HIF pathway [PMID 17905609]
• GRASP55 may function as an adaptor protein coupling MT1-MMP with furin, thus leading to the activation of the zymogen. [PMID 20608975]
• The authors found that partially mature virions incorporating considerable amounts of uncleaved prM protein do not require furin-like proteases for infectivity. [PMID 21880759]
• Activin stimulates endogenous inhibin alpha- and betaB-subunit mRNA, protein, and proteolytic processing. Simultaneously, activin stimulated the proconvertase furin through a Smad2/3-dependent process. [PMID 18826955]
• furin substrate specificity requirements in addition to the motif R-X-K/R-R [PMID 19477160]
• transferrin receptor 2 and HFE are involved in holotransferrin-dependent signaling for the regulation of furin which involved Erk phosphorylation. Furin in turn may control hepcidin expression. [PMID 20634490]
• Reconstituted Complex; Two-hybrid [PMID 9695949]
• PAI-1 forms stable complex with furin, which leads to the inhibition of the intra-Golgi activity of furin. [PMID 21406565]
• furin can directly cleave the RXXR amino acid sequence in the propeptide domain of proMMP-2 leading to inactivation of the enzyme. [PMID 15637056]
• s-HJV originates from a furin cleavage at position 332-335 [PMID 17938254]
• findings established the existence of a novel alternative/complementary pathway by which furin increases tumor cell invasion through an amplification/activation loop between MMP-2 and TGFbeta [PMID 14644155]
• Affinity Capture-Western; Reconstituted Complex; Two-hybrid [PMID 9412467]
• These data support the hypothesis of a direct binding of heparin with site1 and site2, allowing selective exposure/accessibility of the REKR sequence, which is only then optimally cleaved by furin. [PMID 18037384]
• Affinity Capture-MS [PMID 21890473]
• PCSK9 levels are finely regulated by the basic amino acid convertases furin and PC5/6A [PMID 16912035]
• Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 20628086]
• Furin cleaves HIV-1 Tat at amino acid residue 56, resulting in greatly reduced Tat transactivation activity [PMID 15135058]
• involvement of the proximal GATA recognition motif in the P1 promoter and impact on the maturation of furin substrates of Furin gene regulation in differentiating megakaryoblastic cells. [PMID 12411321]
• Furin interacts with ADAMTS4. [PMID 14744861]
• Using siRNA approach the demonstrated that hepatitis C virus-induced furin and thrombospondin-1 (TSP-1) are involved in the proteolytic activation of TGF-beta1. [PMID 21296375]
• The furin hydrolysis of the peptides was activated between 60- and 80-fold by MgCl. [PMID 20635860]
• pro-ADAMTS9 is processed at the cell surface by furin [PMID 16537537]
• the interaction between the PTB domain of Mint3 and the acidic peptide signal of Furin regulates the specific localization of Furin in the trans-Golgi network [PMID 18544638]
• fibrates simultaneously decreased PCSK9 expression while increasing PC5/6A and furin expression, indicating a broad action of PPARalpha activation in proprotein convertase-mediated lipid homeostasis. [PMID 18245819]
• From a brain cDNA library of possible interacting proteins, furin efficiently processes both the beta-secretase beta-amyloid protein converting enzyme pro-BACE1 and its novel interacting partner brain-specific type II membrane protein pro-BRI3. [PMID 15606899]
• These findings highlight a pivotal role for furin, MT1-MMP, and MMP2 in TNF-alpha-induced sphingolipid signaling, and they identify this system as a possible target to inhibit SMC proliferation in vascular diseases. [PMID 17283058]
• This study provides valuable insights into the structural properties of the furin prodomain in relation to its role in the folding of the furin zymogen and its inhibitory action toward furin. [PMID 17477394]
• common SNP in the P1 promoter of the Fur gene affects furin transcription activity and HBV infection outcome, possibly by increasing furin messenger RNA expression. [PMID 19492430]
• furin and PC5 play a role in a MT-MMP-MMP-2 proteolytic cascade, involving provision of macrophage MT1-MMP for the activation of pro-MMP-2; furin and PC5 are expressed in monocytes and colocalize with MT1-MMP in macrophages in the atherosclerotic plaque [PMID 15911696]
• furin is responsible for VEGF-C processing in human oral tongue squamous cell carcinoma progression [PMID 15240540]
• modelling of furin’s pro-region revealed that Ile-60 and His-66 might be crucial in forming the binding interface with the catalytic domain, while residues Trp-34 and Phe-67 might be involved in maintaining a hydrophobic core within the pro-region itself [PMID 14741044]
• Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10. [PMID 21550985]
• Furin-resistant Sema3E inhibits endothelial cells and hampers tumour angiogenesis and tumour growth. [PMID 22247010]
• serpin/furin complex stability depends on pH and regulation at the deacylation step [PMID 15659365]
• level of furin expression in Colo16 cells correlated to changes in pp38 levels in the cells following exposure to UV radiation [PMID 19152512]
• CysLT1 is involved in remodeling processes through modulation of furin transcription. [PMID 18323532]
• Furin, a subtilisin-like eukaryotic endoprotease, is able to process HIV-1 gp160/gp140 to the cleavage products gp120 and gp41 at the cleavage site with the consensus amino acid sequence Arg-X-Lys/Arg-Arg [PMID 16600625]
• enzymatic activity of furin is critical to render the internalized immature dengue virus infectious [PMID 20062797]
• Reconstituted Complex [PMID 9442015]
• increased levels of soluble Axl and Mer were associated with increased levels of mature ADAM17, mature ADAM10, and Furin [PMID 19541935]
• IL-12 caused Furin to be preferentially expressed in differentiated Th1 cells in a Stat4-dependent manner [PMID 16627761]
• Furin may constitute a marker for ovarian tumor progression and could contribute to predict the outcome of this disease. [PMID 17641413]
• Furin mediates cleavage of a receptor tyrosine phosphatase and regulation of beta catenin’s transcriptional activity. [PMID 16648485]
• an amino acid substitution in the PC1/3 propeptide can induce significant modifications of its inhibitory profile toward furin [PMID 16407210]
• in hepatocytes furin regulates PCSK9 mRNA levels and is the key in vivo-inactivating protease of circulating PCSK9. [PMID 21147780]
• Data suggest that furin levels in cystic fibrosis respiratory epithelial cells contributes to bacterial toxin-induced cell death, fibrosis, and local immunosuppression. [PMID 17948127]
• Furin P1A promoter undergoes transactivation via Sox9 binding during chondrogenesis. [PMID 17360815]
• HEPC MISSENSE MUTATION CAUSING INEFFICIENT CLEAVAGE INDICATES THAT THE FURIN BINDING SITE BE MORE THAN 4 RESIDUES [PMID 17905608]
• T(3) regulates furin gene expression via a novel mechanism or in cooperation with TGF-beta to enhance tumor metastasis in vitro and in vivo. [PMID 18467449]
• Our results suggest that the FURIN gene may be a candidate gene involved in human hypertension, and that the G allele of 1970C > G may be a modest risk factor for hypertension in Xinjiang Kazakh and Uygur populations. [PMID 20707915]
• Observational study of gene-disease association. (HuGE Navigator) [PMID 20707915]
• Processing of CD109 into 180 kDa and 25 kDa proteins by furin, followed by complex formation with the type I TGF-beta receptor is required for the regulation of TGF-beta signaling in cancer cells and keratinocytes. [PMID 20101215]
• Furin proteolytically processes the heparin-binding region of extracellular superoxide dismutase [PMID 11861638]
• role in Semliki Forest virus p62 processing [PMID 12584323]
• results show that shedding of furin occurs rapidly and further suggest that specific cysteine residues may impart a conformation to the enzyme, thereby affecting its susceptibility to proteolysis [PMID 12220680]
• PC furin is a major IGF-1 receptor convertase. [PMID 18064302]
• Reconstituted Complex [PMID 10593987]
• Results report the identification of Spn4A, a previously uncharacterized secretory pathway serine protease inhibitor (serpin) from Drosophila melanogaster that contains a consensus furin cleavage site. [PMID 15247425]
• The Ca2+-binding capacity of epidermal furin is disrupted by H2O2-mediated oxidation in vitiligo. [PMID 18174282]
• These observations support the notion that hypoxia promotes the formation of a peripheral processing compartment where furin translocates for enhanced processing of proproteins involved in tumorigenesis. [PMID 21503879]
• Furin expression was found to be increased in salivary glands of Sjogren’s syndrome patients. [PMID 20811902]

PubMed Articles

Recent articles:

• Casazza A et al. “Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform.” EMBO Mol Med. 2012 Mar;4(3):234-50. PMID 22247010
• Arsenault D et al. “Hypoxia enhances cancer cell invasion through relocalization of the proprotein convertase furin from the trans-Golgi network to the cell surface.” J Cell Physiol. 2012 Feb;227(2):789-800. PMID 21503879
• Turpeinen H et al. “Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL.” Atherosclerosis. 2011 Dec;219(2):799-806. PMID 21889147
• Mukherjee S et al. “The infectivity of prM-containing partially mature West Nile virus does not require the activity of cellular furin-like proteases.” J Virol. 2011 Nov;85(22):12067-72. PMID 21880759
• Wagner SA et al. “A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.” Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. PMID 21890473
• Ehret GB et al. “Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.” Nature. 2011 Sep 11;478(7367):103-9. PMID 21909115
• Susan-Resiga D et al. “Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10.” J Biol Chem. 2011 Jul 1;286(26):22785-94. PMID 21550985
• Bernot D et al. “Plasminogen activator inhibitor 1 is an intracellular inhibitor of furin proprotein convertase.” J Cell Sci. 2011 Apr 15;124(Pt 8):1224-30. PMID 21406565
• Presser LD et al. “Hepatitis C virus-induced furin and thrombospondin-1 activate TGF-β1: role of TGF-β1 in HCV replication.” Virology. 2011 Apr 10;412(2):284-96. PMID 21296375
• Essalmani R et al. “In vivo evidence that furin from hepatocytes inactivates PCSK9.” J Biol Chem. 2011 Feb 11;286(6):4257-63. PMID 21147780

Top Pubmed articles linked to gene FURIN matching any search term:

• Niessen SJ et al. “Novel diabetes mellitus treatment: mature canine insulin production by canine striated muscle through gene therapy.” Domest Anim Endocrinol. 2012 Jul;43(1):16-25. PMID 22405830
• Elsner M et al. “Reversal of diabetes through gene therapy of diabetic rats by hepatic insulin expression via lentiviral transduction.” Mol Ther. 2012 May;20(5):918-26. PMID 22354377
• Fu J et al. “Transgenic overexpression of the proprotein convertase furin enhances skin tumor growth.” Neoplasia. 2012 Apr;14(4):271-82. PMID 22577343
• Kim JH et al. “Potential of nucleofected human MSCs for insulin secretion.” J Tissue Eng Regen Med. 2011 Nov;5(10):761-9. PMID 22002919
• Jean M et al. “Effective and safe gene-based delivery of GLP-1 using chitosan/plasmid-DNA therapeutic nanocomplexes in an animal model of type 2 diabetes.” Gene Ther. 2011 Aug;18(8):807-16. PMID 21412280
• Boyhan D et al. “Low-cost production of proinsulin in tobacco and lettuce chloroplasts for injectable or oral delivery of functional insulin and C-peptide.” Plant Biotechnol J. 2011 Jun;9(5):585-98. PMID 21143365
• Bernot D et al. “Plasminogen activator inhibitor 1 is an intracellular inhibitor of furin proprotein convertase.” J Cell Sci. 2011 Apr 15;124(Pt 8):1224-30. PMID 21406565
• Han J et al. “Remission of diabetes by insulin gene therapy using a hepatocyte-specific and glucose-responsive synthetic promoter.” Mol Ther. 2011 Mar;19(3):470-8. PMID 21119621
• Gyamera-Acheampong C et al. “The precursor to the germ cell-specific PCSK4 proteinase is inefficiently activated in transfected somatic cells: evidence of interaction with the BiP chaperone.” Mol Cell Biochem. 2011 Feb;348(1-2):43-52. PMID 21080038
• Bailey SD et al. “Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.” Diabetes Care. 2010 Oct;33(10):2250-3. PMID 20628086
• Oida T et al. “Overexpression of TGF-ß 1 gene induces cell surface localized glucose-regulated protein 78-associated latency-associated peptide/TGF-ß.” J Immunol. 2010 Sep 15;185(6):3529-35. PMID 20720212
• Scamuffa N et al. “Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells.” J Clin Invest. 2008 Jan;118(1):352-63. PMID 18064302
• López de Cicco R et al. “Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin.” Cancer Res. 2005 May 15;65(10):4162-71. PMID 15899807
• Herz J et al. “Proteolytic processing of the 600 kd low density lipoprotein receptor-related protein (LRP) occurs in a trans-Golgi compartment.” EMBO J. 1990 Jun;9(6):1769-76. PMID 2112085
• Roebroek AJ et al. “Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein.” EMBO J. 1986 Sep;5(9):2197-202. PMID 3023061