FURIN (furin (paired basic amino acid cleaving enzyme))
2012-04-01 Abdel-Majid Khatib , Fatma Sfaxi AffiliationUniversity Bordeaux 1, INSERM U1029, Avenue des Facultes, Batiment B2, Talence 33405, France
Identity
HGNC
LOCATION
15q26.1
LOCUSID
ALIAS
FUR,PACE,PCSK3,SPC1
FUSION GENES
DNA/RNA
Description
This gene can be found on chromosome 15 at location: 89212826-89227692.
Transcription
The DNA sequence contains 16 exons and the transcript length: 4244 bps translated to a 794 residues protein.
Proteins
Description
Furin is a member of the family of subtilisin/kexin-like proprotein convertases (PCs) that process protein at basic residues. This protein is produced as a 104 kDa zymogen that is converted into a 98 kDa mature following autocatalytic cleavage at two sites. The cleavages occur during enzyme progression from the endoplasmic reticulum to the trans golgi network (TGN).
Expression
Expression of Furin in different tissues was localized by northern blot, in situ hybridization and histochemistry. These analyses demonstrated that Furin is ubiquitously expressed. However, high expression of Furin was found in liver and spleen.
Localisation
Furin cycle between the cell surface and the TGN.
Function
Furin is involved in the activation of precursor proteins by cleavage on a single or paired basic residue. Precursors are usually cleaved at the general motif (K/R)-(X)n-(K/R)↓, where n= 0, 2, 4 or 6. Furin substrates include growth factors and their receptors (such as pro-TGFb, pro-IGF-1, 2, pro-PDGF-A, B, insulin-R, IGF1-R, R-PTPm, Notch), neurotrophins (pro-NGF, -BDNF,- NT3), prohormones (pro-PTH, pro-endothelin, proparathyroid hormone), blood coagulation factors (pro-Von Willebrand Factor, pro-Factor VII, pro-Factor IX, pro-Factor X), integrins (α3, α6, αv, α5 and α4 chains) and various metalloendopeptidases (stromelysin-3, ADAM, ADAMTS, MT1-MMP). The activation of these substrates by Furin, implicated directly the latter to cell proliferation, survival, migration, invasion and homeostasis.
Homology
The Furin catalytic domain has a high percentage of homology with those of the other PCs which range from 70% (between PACE4 and Furin) to 54% (between PC2 and Furin).
Implicated in
Entity name
Cancer
Note
To date Furin is expressed in all tissues and cell lines examined so far but at very low levels as compared to tumor cells and tissues. Inhibition of Furin activity or expression in tumor cells reduced dramatically their malignant phenotype (proliferation, invasion, migration...) and their ability to induce tumor growth.
Entity name
Head and neck squamous cell carcinomas (HNSCCs)
Note
While Furin expression is undetectable in non metastasing head and neck squamous cell carcinomas its overexpressed in more aggressive lines.
Entity name
Ovarian epithelial cancer
Note
A comparative study of the Furin expression between normal human ovarian surface epithelium and cancer cell lines as well as ovarian epithelial cancer specimens revealed that Furin is only expressed in cancer cell lines especially in primary tumors from patients whose life expectancy dont exceed five years.
Entity name
Oral tongue squamous cell carcinoma
Note
The Furin expression was found to be correlated with the grade of oral tongue squamous carcinoma. The highest Furin expression was found in the most aggressive line of squamous cell carcinoma (SCC) and the least Furin expression in the less aggressive line.
Entity name
Breast cancer
Note
Furin was shown to be overexpressed in breast cancer cell lines and breast tumor tissues.
Entity name
Viral infections
Note
By activating various viral envelope glycoproteins, Furin is involved in numerous viral infections. These include HIV-gp160, RSV-Pr95env, NDV-F, Influenza haemagglutinin-HA, CMV-gB, SFV-p62.
Entity name
Bacterial infections
Note
The involvement of Furin in bacterial infections was suggested by its capacity to activate the various classes of bacterial toxins such as the Diphteria toxin, Pseudomonas Aerugenosa exotoxin A, Botulinum neurotoxin, Bordetella dermonecrotic toxin, Anthrax and aerolysin.
Entity name
Neurodegenerative pathology
Note
Furin can activate the α and β-secretase which are implicated in the cleavage of amyloid-β the principal component of senile plaques.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 16648485 | 2006 | Furin-, ADAM 10-, and gamma-secretase-mediated cleavage of a receptor tyrosine phosphatase and regulation of beta-catenin's transcriptional activity. | Anders L et al |
| 11799113 | 2002 | The ordered and compartment-specfific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation. | Anderson ED et al |
| 16102752 | 2005 | Modulating furin activity with designed mini-PDX peptides: synthesis and in vitro kinetic evaluation. | Basak A et al |
| 11517338 | 2001 | Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells. | Bassi DE et al |
| 12547702 | 2003 | Increased furin activity enhances the malignant phenotype of human head and neck cancer cells. | Bassi DE et al |
| 12691605 | 2003 | Processing of alpha4 integrin by the proprotein convertases: histidine at position P6 regulates cleavage. | Bergeron E et al |
| 11861826 | 2002 | Enhancing the proteolytic maturation of human immunodeficiency virus type 1 envelope glycoproteins. | Binley JM et al |
| 21112328 | 2011 | Development and characterisation of an assay for furin activity. | Bourne GL et al |
| 15637056 | 2005 | Furin directly cleaves proMMP-2 in the trans-Golgi network resulting in a nonfunctioning proteinase. | Cao J et al |
| 22247010 | 2012 | Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. | Casazza A et al |
| 18467449 | 2008 | Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines. | Chen RN et al |
| 19995186 | 2009 | The role of furin in papillomavirus infection. | Day PM et al |
| 19642690 | 2009 | In vivo bioluminescence imaging of furin activity in breast cancer cells using bioluminogenic substrates. | Dragulescu-Andrasi A et al |
| 7737999 | 1995 | Processing of transforming growth factor beta 1 precursor by human furin convertase. | Dubois CM et al |
| 18544638 | 2008 | Interaction of Mint3 with Furin regulates the localization of Furin in the trans-Golgi network. | Han J et al |
| 10887202 | 2000 | Characterization of Alzheimer's beta -secretase protein BACE. A pepsin family member with unusual properties. | Haniu M et al |
| 16942750 | 2006 | Furin is an endogenous regulator of alpha-secretase associated APP processing. | Hwang EM et al |
| 17179036 | 2006 | Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine. | Jiao GS et al |
| 18712106 | 2007 | [Furin and its biological role]. | Kibirev VK et al |
| 15371436 | 2004 | Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection. | Kibler KV et al |
| 1741956 | 1991 | Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15. | Kiefer MC et al |
| 20980434 | 2010 | p38 kinase is crucial for osteopontin-induced furin expression that supports cervical cancer progression. | Kumar V et al |
| 10373500 | 1999 | ADAMTS-1 is an active metalloproteinase associated with the extracellular matrix. | Kuno K et al |
| 17516499 | 2008 | The structure of the TGF-beta latency associated peptide region determines the ability of the proprotein convertase furin to cleave TGF-betas. | Kusakabe M et al |
| 17909005 | 2007 | Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells' malignant phenotypes: role of tissue inhibitors of metalloproteinase-1. | Lapierre M et al |
| 19492430 | 2009 | Influence of a single nucleotide polymorphism in the P1 promoter of the furin gene on transcription activity and hepatitis B virus infection. | Lei RX et al |
| 19385064 | 2009 | Loss-of-function point mutations and two-furin domain derivatives provide insights about R-spondin2 structure and function. | Li SJ et al |
| 10657249 | 2000 | Endoproteolytic processing of integrin pro-alpha subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7. | Lissitzky JC et al |
| 7539217 | 1995 | Processing of pro-PTHRP by the prohormone convertase, furin: effect on biological activity. | Liu B et al |
| 9642263 | 1998 | Human ADAM 12 (meltrin alpha) is an active metalloprotease. | Loechel F et al |
| 9653148 | 1998 | The Notch1 receptor is cleaved constitutively by a furin-like convertase. | Logeat F et al |
| 15899807 | 2005 | Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. | López de Cicco R et al |
| 22479394 | 2012 | The tyrosine kinase c-Src directly mediates growth factor-induced Notch-1 and Furin interaction and Notch-1 activation in pancreatic cancer cells. | Ma YC et al |
| 12665557 | 2003 | Furin interacts with proMT1-MMP and integrin alphaV at specialized domains of renal cell plasma membrane. | Mayer G et al |
| 9166946 | 1997 | Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. | Mbikay M et al |
| 15611046 | 2005 | Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. | McMahon S et al |
| 14644155 | 2003 | Alternative pathway for the role of furin in tumor cell invasion process. Enhanced MMP-2 levels through bioactive TGFbeta. | McMahon S et al |
| 1644824 | 1992 | Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen. | Molloy SS et al |
| 7508380 | 1994 | Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface. | Molloy SS et al |
| 11921231 | 2002 | Structural investigation of the HIV-1 envelope glycoprotein gp160 cleavage site. | Oliva R et al |
| 17948127 | 2007 | Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity. | Ornatowski W et al |
| 17641413 | 2007 | Increased expression of the pro-protein convertase furin predicts decreased survival in ovarian cancer. | Page RE et al |
| 18037384 | 2007 | Heparin enhances the furin cleavage of HIV-1 gp160 peptides. | Pasquato A et al |
| 21993886 | 2012 | TMPRSS4-dependent activation of the epithelial sodium channel requires cleavage of the γ-subunit distal to the furin cleavage site. | Passero CJ et al |
| 21152186 | 2011 | Furin Functions as a Nonproteolytic Chaperone for Matrix Metalloproteinase-28: MMP-28 Propeptide Sequence Requirement. | Pavlaki M et al |
| 16627761 | 2006 | Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma. | Pesu M et al |
| 9827567 | 1998 | Proprotein cleavage of E-cadherin by furin in baculovirus over-expression system: potential role of other convertases in mammalian cells. | Posthaus H et al |
| 16636666 | 2006 | Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP. | Remacle AG et al |
| 3023061 | 1986 | Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein. | Roebroek AJ et al |
| 18064302 | 2008 | Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells. | Scamuffa N et al |
| 8615794 | 1996 | Cellular processing of the nerve growth factor precursor by the mammalian pro-protein convertases. | Seidah NG et al |
| 22186789 | 2012 | Phase I trial of "bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer. | Senzer N et al |
| 21152867 | 2011 | A novel recombinant immuno-tBid with a furin site effectively suppresses the growth of HER2-positive osteosarcoma cells in vitro. | Shan LQ et al |
| 22038627 | 2012 | The non-receptor tyrosine kinase c-Src mediates the PDGF-induced association between Furin and pro-MT1-MMP in HPAC pancreatic cells. | Shi C et al |
| 12670890 | 2003 | The proteolytic processing of pro-platelet-derived growth factor-A at RRKR(86) by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity. | Siegfried G et al |
| 21168329 | 2011 | New furin inhibitors based on weakly basic amidinohydrazones. | Sielaff F et al |
| 22390935 | 2012 | Proprotein convertases in post-menopausal endometrial cancer: distinctive regulation and non-invasive diagnosis. | Singh H et al |
| 15756593 | 2005 | Immunohistochemical localization of subtilisin/kexin-like proprotein convertases in human atherosclerosis. | Stawowy P et al |
| 15911696 | 2005 | Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis. | Stawowy P et al |
| 22113169 | 2012 | Constitutive stimulation of vascular smooth muscle cells by angiotensin II derived from an adenovirus encoding a furin-cleavable fusion protein. | Takayanagi T et al |
| 22340500 | 2012 | SKI-1 and Furin generate multiple RGMa fragments that regulate axonal growth. | Tassew NG et al |
| 17283058 | 2007 | Role for furin in tumor necrosis factor alpha-induced activation of the matrix metalloproteinase/sphingolipid mitogenic pathway. | Tellier E et al |
| 10593987 | 1999 | Recycling of furin from the plasma membrane. Functional importance of the cytoplasmic tail sorting signals and interaction with the AP-2 adaptor medium chain subunit. | Teuchert M et al |
| 22355773 | 2012 | Computational prediction of furin cleavage sites by a hybrid method and understanding mechanism underlying diseases. | Tian S et al |
| 15135058 | 2004 | Furin cleavage of the HIV-1 Tat protein. | Tikhonov I et al |
| 17905609 | 2008 | Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. | Valore EV et al |
| 15584904 | 2004 | BCL-2-induced glioma cell invasiveness depends on furin-like proteases. | Wick W et al |
| 2251280 | 1990 | Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site. | Wise RJ et al |
| 22258248 | 2012 | Mutation of the f-protein cleavage site of avian paramyxovirus type 7 results in furin cleavage, fusion promotion, and increased replication in vitro but not increased replication, tissue tropism, or virulence in chickens. | Xiao S et al |
| 10888676 | 2000 | Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases. | Yana I et al |
| 19853298 | 2009 | The proprotein convertase furin in human trophoblast: Possible role in promoting trophoblast cell migration and invasion. | Zhou Z et al |
Other Information
Locus ID:
NCBI: 5045
MIM: 136950
HGNC: 8568
Ensembl: ENSG00000140564
Variants:
dbSNP: 5045
ClinVar: 5045
TCGA: ENSG00000140564
COSMIC: FURIN
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38330730 | 2024 | The subtilisin-like protease furin regulates hemin-induced CD63 surface expression on platelets. | 0 |
| 38403160 | 2024 | The impact of wound-healing assay, phorbol myristate acetate (PMA) stimulation and siRNA-mediated FURIN gene silencing on endogenous retroviral ERVW-1 expression level in U87-MG astrocytoma cells. | 1 |
| 38489333 | 2024 | Pathological changes in oral epithelium and the expression of SARS-CoV-2 entry receptors, ACE2 and furin. | 0 |
| 38570613 | 2024 | Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations. | 1 |
| 38330730 | 2024 | The subtilisin-like protease furin regulates hemin-induced CD63 surface expression on platelets. | 0 |
| 38403160 | 2024 | The impact of wound-healing assay, phorbol myristate acetate (PMA) stimulation and siRNA-mediated FURIN gene silencing on endogenous retroviral ERVW-1 expression level in U87-MG astrocytoma cells. | 1 |
| 38489333 | 2024 | Pathological changes in oral epithelium and the expression of SARS-CoV-2 entry receptors, ACE2 and furin. | 0 |
| 38570613 | 2024 | Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations. | 1 |
| 36134483 | 2023 | SERPINB8 and furin regulate ITGAX expression and affect the proliferation and invasion of melanoma cells. | 1 |
| 36581038 | 2023 | Proteolytic activation of human-specific Olduvai domains by the furin protease. | 1 |
| 36799665 | 2023 | Overexpression of the pro-protein convertase furin predicts prognosis and promotes papillary thyroid carcinoma progression and metastasis through RAF/MEK signaling. | 3 |
| 37093709 | 2023 | FURIN suppresses the progression of atherosclerosis by promoting macrophage autophagy. | 4 |
| 37105924 | 2023 | Proprotein Convertase Furin Regulates Melanogenesis via the Notch Signaling Pathway. | 0 |
| 37239341 | 2023 | PCSK3 Overexpression in Sjögren's Syndrome Patients May Be Regulated by rs4932178 SNP in Its Promoter Region and Correlates with IFN-γ Gene Expression. | 0 |
| 37443715 | 2023 | Allele-Specific Epigenetic Regulation of FURIN Expression at a Coronary Artery Disease Susceptibility Locus. | 1 |
Citation
Abdel-Majid Khatib ; Fatma Sfaxi
FURIN (furin (paired basic amino acid cleaving enzyme))
Atlas Genet Cytogenet Oncol Haematol. 2012-04-01
Online version: http://atlasgeneticsoncology.org/gene/40646/
