FURIN (furin (paired basic amino acid cleaving enzyme))

2012-04-01 Abdel-Majid Khatib , Fatma Sfaxi Affiliation

University Bordeaux 1, INSERM U1029, Avenue des Facultes, Batiment B2, Talence 33405, France

Identity

HGNC

FURIN

LOCATION

15q26.1

LOCUSID

5045

ALIAS

FUR,PACE,PCSK3,SPC1

FUSION GENES

Show Gene Fusions

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.

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

Gene ID	Transcript ID	Uniprot
ENSG00000140564	ENST00000268171	P09958
ENSG00000140564	ENST00000268171	A0A024RC70
ENSG00000140564	ENST00000558794	H0YNB5
ENSG00000140564	ENST00000559353	H0YKB2
ENSG00000140564	ENST00000560824	H0YLH7
ENSG00000140564	ENST00000610579	P09958
ENSG00000140564	ENST00000610579	A0A024RC70
ENSG00000140564	ENST00000618099	P09958
ENSG00000140564	ENST00000618099	A0A024RC70
ENSG00000140564	ENST00000640725	A0A1W2PPZ9

Expression (GTEx)

100

150

200

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Influenza A	KEGG	ko05164
Influenza A	KEGG	hsa05164
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Gamma carboxylation, hypusine formation and arylsulfatase activation	REACTOME	R-HSA-163841
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	REACTOME	R-HSA-159854
Removal of aminoterminal propeptides from gamma-carboxylated proteins	REACTOME	R-HSA-159782
Disease	REACTOME	R-HSA-1643685
Infectious disease	REACTOME	R-HSA-5663205
HIV Infection	REACTOME	R-HSA-162906
HIV Life Cycle	REACTOME	R-HSA-162587
Late Phase of HIV Life Cycle	REACTOME	R-HSA-162599
Assembly Of The HIV Virion	REACTOME	R-HSA-175474
Synthesis and processing of ENV and VPU	REACTOME	R-HSA-171286
Uptake and actions of bacterial toxins	REACTOME	R-HSA-5339562
Uptake and function of anthrax toxins	REACTOME	R-HSA-5210891
Amyloid fiber formation	REACTOME	R-HSA-977225
Signal Transduction	REACTOME	R-HSA-162582
Signalling by NGF	REACTOME	R-HSA-166520
NGF processing	REACTOME	R-HSA-167060
Signaling by PDGF	REACTOME	R-HSA-186797
Signaling by TGF-beta Receptor Complex	REACTOME	R-HSA-170834
TGF-beta receptor signaling activates SMADs	REACTOME	R-HSA-2173789
Signaling by NOTCH	REACTOME	R-HSA-157118
Pre-NOTCH Expression and Processing	REACTOME	R-HSA-1912422
Pre-NOTCH Processing in Golgi	REACTOME	R-HSA-1912420
Metabolism	REACTOME	R-HSA-1430728
Metabolism of lipids and lipoproteins	REACTOME	R-HSA-556833
Lipid digestion, mobilization, and transport	REACTOME	R-HSA-73923
Lipoprotein metabolism	REACTOME	R-HSA-174824
Chylomicron-mediated lipid transport	REACTOME	R-HSA-174800
Extracellular matrix organization	REACTOME	R-HSA-1474244
Elastic fibre formation	REACTOME	R-HSA-1566948
Degradation of the extracellular matrix	REACTOME	R-HSA-1474228
Activation of Matrix Metalloproteinases	REACTOME	R-HSA-1592389
Collagen degradation	REACTOME	R-HSA-1442490
Developmental Biology	REACTOME	R-HSA-1266738
Signaling by NODAL	REACTOME	R-HSA-1181150
Keratinization	REACTOME	R-HSA-6805567
Formation of the cornified envelope	REACTOME	R-HSA-6809371

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
20062797	2010	Immature dengue virus: a veiled pathogen?	107
17938254	2008	Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis.	97
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
16912035	2006	The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.	74
17905609	2008	Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin.	50
12584323	2003	Furin processing and proteolytic activation of Semliki Forest virus.	46
15611046	2005	Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins.	43
12736257	2003	Furin-mediated processing of Pro-C-type natriuretic peptide.	41
21147780	2011	In vivo evidence that furin from hepatocytes inactivates PCSK9.	41
16648485	2006	Furin-, ADAM 10-, and gamma-secretase-mediated cleavage of a receptor tyrosine phosphatase and regulation of beta-catenin's transcriptional activity.	40

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/furin