Affinage

FURIN

Furin · UniProt P09958

Length
794 aa
Mass
86.7 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Furin is a subtilisin-like serine proprotein convertase that catalyzes the maturation of a broad range of secretory-pathway substrates by cleaving C-terminal to paired/polybasic Arg-X-X-Arg motifs, with site recognition validated by P1 Arg mutagenesis and pharmacological inhibition (alpha1-PDX) across substrates such as pro-vWF, pro-factor IX, and Notch1 (PMID:2094803, PMID:8473289, PMID:9653148). Its co-crystal structures with peptidomimetic inhibitors define how the active site engages polybasic substrate residues (PMID:25974265). Functionally, furin maturates growth factors and morphogens (BMP-4, TGF-beta1, GDF15), receptors and adhesion molecules (Notch1, IGF-1R, N-cadherin, CD109), matrix and circulating proteins (ADAMTS9, EC-SOD, PCSK9, lipoprotein lipase), and is hijacked by pathogens to activate Shiga toxin and viral envelope glycoproteins including the SARS-CoV-2 spike at the S1/S2 and S2' sites (PMID:7738018, PMID:9707432, PMID:11141505, PMID:11861638, PMID:16537537, PMID:20101215, PMID:21147780, PMID:23598405, PMID:30021841, PMID:30104250, PMID:33494095, PMID:35343766). Furin can act in distinct subcellular compartments—intracellularly in the Golgi/secretory pathway or at the cell surface—with substrate site selection sometimes guided by chaperone-like partners such as Cripto for Nodal (PMID:11861638, PMID:16537537, PMID:18772886). TGF-beta1 establishes a feed-forward loop by transcriptionally inducing furin through Smad2/4 signaling at its P1 promoter, one of three alternative promoters (P1, P1A, P1B) that, together with transcription factors C/EBP-beta, SP1, and CDX2, tune furin expression in a tissue- and differentiation-specific manner (PMID:8132667, PMID:11141505, PMID:11424093, PMID:16239403). In vivo, furin is essential for endothelial-dependent cardiac morphogenesis, trophoblast syncytialization via IGF1R processing, hepatic inactivation of PCSK9 with consequent control of LDL receptor levels, myeloid anti-inflammatory homeostasis, and neuronal plasticity through BDNF-ERK-CREB signaling (PMID:21147780, PMID:22733989, PMID:23598405, PMID:27527873, PMID:29302702).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1990 High

    Establishing furin's basic enzymatic identity answered whether the FUR gene product is a protease and what it recognizes, founding the proprotein convertase concept.

    Evidence Cotransfection of FUR cDNA with pro-vWF in COS-1 cells plus P1 Arg mutagenesis

    PMID:2094803

    Open questions at the time
    • Did not define subcellular site of cleavage
    • Substrate repertoire beyond pro-vWF unknown at this point
  2. 1993 High

    Reconstitution of pro-factor IX processing showed furin acts at authentic physiological propeptide sites within the secretory pathway and is distinguishable from PACE4, validating it as a bona fide maturation enzyme.

    Evidence Co-transfection in CHO cells with N-terminal sequencing, pulse-chase, cleavage-site mutagenesis, and alpha1-PDX inhibition

    PMID:8473289

    Open questions at the time
    • Endogenous vs. overexpressed enzyme contribution not separated
    • Compartment of cleavage not directly localized
  3. 1994 High

    Mapping three alternative promoters answered how furin expression is transcriptionally diversified, linking enzyme levels to specific transcription factors.

    Evidence Primer extension, luciferase reporters, EMSA, and DNase I footprinting of the human FUR gene

    PMID:8132667

    Open questions at the time
    • Tissue-specific promoter usage not resolved in vivo
    • Upstream signals controlling each promoter only partially defined
  4. 1995 High

    Showing furin is required for Shiga toxin A-chain nicking established that pathogens exploit furin proteolysis for activation, extending its substrate scope beyond host proproteins.

    Evidence In vitro digestion with soluble furin plus genetic complementation of furin-deficient LoVo cells and toxicity assay

    PMID:7738018

    Open questions at the time
    • Did not establish which compartment cleaves toxin in intact cells
    • Other PCs' redundant contribution not excluded
  5. 1998 High

    Identifying Notch1 and BMP-4 as furin substrates connected the convertase to receptor maturation and developmental morphogen signaling.

    Evidence LoVo complementation, alpha1-PDX, in vitro digestion, and cleavage-site mutagenesis for Notch1; Xenopus epistasis and oocyte translation assays for BMP-4

    PMID:9653148 PMID:9707432

    Open questions at the time
    • Redundancy with PC6B for BMP-4 not fully resolved
    • In vivo requirement for Notch1 processing not tested genetically here
  6. 2001 High

    Defining furin as the principal TGF-beta1-converting enzyme and showing TGF-beta1 induces furin via Smad2/4 revealed a feed-forward regulatory loop coupling enzyme abundance to its own substrate pathway.

    Evidence alpha1-PDX inhibition and LoVo complementation with bioactivity readout; P1 promoter reporter assays with dominant-negative Smads

    PMID:11141505 PMID:11424093

    Open questions at the time
    • Direct Smad binding to the fur promoter not shown by ChIP
    • Quantitative contribution of loop to physiology untested
  7. 2002 High

    Localizing EC-SOD cleavage to a pre-secretory intracellular step showed furin processing can determine substrate tissue distribution and half-life, not just activation.

    Evidence Furin overexpression, in vitro digestion of purified EC-SOD, Arg213 mutagenesis, and secretory-pathway inhibitors

    PMID:11861638

    Open questions at the time
    • Identity of the downstream carboxypeptidase not defined
    • In vivo physiological consequence not tested
  8. 2004 Medium

    Crystallographic determination of the furin catalytic core provided the structural basis for polybasic substrate recognition and serine protease catalysis.

    Evidence X-ray crystallography of the catalytic core domain (review summary)

    PMID:15102434

    Open questions at the time
    • Review rather than primary structure report
    • Conformational changes upon substrate binding not detailed
  9. 2006 Medium

    Demonstrating sequential furin-then-ADAM10/gamma-secretase processing of RPTPkappa and cell-surface processing of pro-ADAMTS9 showed furin initiates multistep proteolytic cascades and can act outside the TGN.

    Evidence Inhibitors, fractionation, reporter assays for RPTPkappa; pulse-chase, furin-null complementation, siRNA for ADAMTS9

    PMID:16537537 PMID:16648485

    Open questions at the time
    • Genetic null confirmation of furin's RPTPkappa role lacking
    • Determinants of TGN vs. surface cleavage not defined
  10. 2008 High

    Showing Cripto directs Nodal to extracellular convertases answered how substrate compartmental routing is controlled, revealing chaperone-guided spatial regulation of furin processing.

    Evidence Reciprocal Co-IP of Cripto with Furin/PACE4 and Nodal, brefeldin A, density fractionation, and signaling readouts

    PMID:18772886

    Open questions at the time
    • Direct furin-Nodal cleavage at the surface not biochemically isolated
    • Generality of Cripto-type routing for other substrates unknown
  11. 2010 High

    Identifying CD109, PCSK9, and furin-OPN signaling expanded furin's roles into TGF-beta receptor regulation, lipid metabolism, and cancer cell motility, including in vivo confirmation of PCSK9 inactivation.

    Evidence Cleavage-site mutagenesis and Co-IP for CD109; hepatocyte-specific KO mice for PCSK9; pathway inhibitors and xenografts for OPN-furin

    PMID:20101215 PMID:20980434 PMID:21147780

    Open questions at the time
    • OPN-furin pathway placement rests on epistasis, not direct binding
    • Only membrane-bound, not soluble, furin shown active on PCSK9
  12. 2012 High

    Endothelial-specific furin knockout demonstrated an essential in vivo role in cardiac morphogenesis and identified ET-1, Adm, and TGF-beta1 as physiological endothelial substrates.

    Evidence Cre-lox endothelial KO with MRI, primary endothelial cultures, soluble furin rescue, and substrate processing analysis

    PMID:22733989

    Open questions at the time
    • Which substrate deficiency drives the cardiac defect not isolated
    • Mechanism of soluble furin rescue of proliferation unresolved
  13. 2013 High

    Furin requirement for trophoblast syncytialization via IGF1R processing, and direct proapelin cleavage, extended furin into placental development and metabolic peptide generation.

    Evidence siRNA, inhibitors, BeWo fusion, lentiviral RNAi in vivo for syncytialization; in vitro PCSK-selectivity cleavage for proapelin

    PMID:23598405 PMID:24251091

    Open questions at the time
    • Proapelin cleavage not confirmed genetically in cells
    • Other substrates contributing to syncytialization not excluded
  14. 2014 Medium

    Establishing furin as the major convertase for KISS1 processing linked it to kisspeptin generation with specificity over PCSK5/7.

    Evidence shRNA specificity comparison across PCSKs plus PC inhibitor treatment in KISS1-overexpressing cells

    PMID:24454770

    Open questions at the time
    • No in vitro reconstitution with purified furin
    • Physiological/in vivo relevance untested
  15. 2015 Medium

    High-resolution inhibitor co-crystallography and characterization of redundant convertase activity on E-cadherin during compaction refined both the druggability of furin and its developmental role in adhesion.

    Evidence Co-crystal structure with MI-1148 and Ki determination; PC mutant embryos with live reporter imaging for E-cadherin

    PMID:25974265 PMID:26416966

    Open questions at the time
    • Furin's individual contribution to E-cadherin processing partly inferential among redundant PCs
    • Inhibitor selectivity over related PCs incomplete
  16. 2016 Medium

    Myeloid-specific furin knockout revealed an anti-inflammatory regulatory role, controlling macrophage polarization and cytokine output partly via TGF-beta1, TACE, and Caspase-1 maturation.

    Evidence LysMCre conditional KO with LPS challenge, serum cytokines, expression profiling, and polarization markers

    PMID:27527873

    Open questions at the time
    • Direct biochemical reconstitution of myeloid substrate cleavage lacking
    • Which substrate dominates the phenotype unresolved
  17. 2018 Medium

    Gain- and loss-of-function studies placed furin in neuronal plasticity (BDNF-ERK-CREB), inhibitory transmission (GABAAR), oocyte maturation (Plac1-IGF1R-Akt), and lipid handling (ANGPTL4-LPL), broadening its physiological repertoire.

    Evidence Furin transgenic/knockdown mice with LTP, memory, electrophysiology, BDNF processing; Co-IP/MS in oocytes; siRNA/KO in adipocytes

    PMID:29302702 PMID:29723063 PMID:30021841 PMID:30333479

    Open questions at the time
    • Several mechanisms inferred from overexpression rather than physiological loss-of-function
    • Transcriptional GABAAR regulation mechanism not elucidated
  18. 2019 Medium

    In vivo gain- and loss-of-function in atherosclerosis models, with GDF15 and MMP2 as substrates, connected furin activity to vascular remodeling and inflammation.

    Evidence alpha1-PDX administration and furin overexpression in Ldlr-/-/Apoe-/- and wire-injury models; MMP2 analysis; in vitro/in vivo GDF15 cleavage by multiple PCSKs

    PMID:30104250 PMID:30651003

    Open questions at the time
    • GDF15 cleavage shared among multiple PCSKs limits furin specificity
    • Causal substrate driving atherosclerosis phenotype not isolated
  19. 2021 High

    Reverse genetics and proteomics established the furin cleavage site in SARS-CoV-2 spike as a determinant of replication and pathogenesis, and defined dual S1/S2 and S2' cleavage enhanced by ACE2 engagement.

    Evidence Spike furin-site deletion mutant in animal models; proteomic S2' site mapping; combined furin/TMPRSS2 inhibition in Calu-3 cells

    PMID:33494095 PMID:35343766

    Open questions at the time
    • Compartment and timing of S2' cleavage in infection not fully resolved
    • Therapeutic translation of dual inhibition untested clinically

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how furin's compartmental routing, substrate selection, and redundancy with other proprotein convertases are coordinated to produce tissue-specific physiological outcomes.
  • No unified model of compartment-specific substrate selectivity
  • Quantitative partitioning of substrates among furin vs. PC5/PC6/PACE4 unknown
  • In vivo substrate hierarchy for most phenotypes unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 5
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 2
Partners
CRIPTOIGF1RPACE4PLAC1TGFBR1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Furin (encoded by the human FUR gene) is a subtilisin-like serine protease with substrate specificity for paired basic residues. Cotransfection of FUR cDNA with pro-von Willebrand factor (pro-vWF) cDNA in COS-1 cells showed increased proteolytic processing of pro-vWF at the Arg-Ser-Lys-Arg site; mutation of the P1 Arg abolished cleavage, establishing furin as a proprotein processing enzyme cleaving after paired basic residues. Cotransfection of COS-1 cells with FUR cDNA and pro-vWF constructs (wild-type and Arg→Gly mutant); Western blot analysis Molecular biology reports High 2094803
1993 PACE/furin (PCSK3) processes pro-factor IX at the authentic propeptide cleavage site within the secretory pathway. Co-transfection of PACE with profactor IX in CHO cells resulted in secretion of fully processed factor IX; PACE4 did not increase processing; an Arg39Thr P1 mutation abolished cleavage; the alpha1-antitrypsin Pittsburgh (PDX) inhibitor blocked furin-mediated processing. Co-transfection in CHO cells; amino-terminal sequence analysis; pulse-chase labeling; specific protease inhibitor (alpha1-PDX) experiments The Journal of biological chemistry High 8473289
1994 Expression of the human FUR gene is directed by three alternative promoters (P1, P1A, P1B) that produce distinct mRNA isoforms differing in their 5'-UTRs. P1 contains a TATA box and is transactivated by C/EBP-beta and bound by SP1; P1A and P1B are GC-rich housekeeping-type promoters. Differential promoter usage modulates furin enzyme levels. Primer extension analysis; luciferase reporter transfection assays; electromobility shift assays; DNase I footprinting The Journal of biological chemistry High 8132667
1995 Furin cleaves Shiga toxin A-chain at the Arg-X-X-Arg motif, generating A1 and A2 fragments, and this cleavage is required for efficient intoxication. LoVo cells (furin-deficient) cleaved intact A-chain very slowly; LoVo cells transfected with furin cleaved it efficiently. Furin-nicked toxin was ~20-fold more active than unnicked toxin in furin-deficient cells. In vitro digestion with soluble furin; transfection of furin into LoVo (furin-deficient) cells; protein synthesis inhibition assay The Journal of biological chemistry High 7738018
1998 Notch1 receptor (300 kDa precursor) is constitutively processed by a furin-like convertase in the extracellular region at the sequence RQRR (aa 1651-1654); only cleaved Notch1 fragments are present at the cell surface. Processing was blocked by alpha1-PDX (furin inhibitor) and calcium ionophore A23187; in furin-deficient LoVo cells, processing did not occur; in vitro digestion with purified furin confirmed the cleavage site; mutation of the four basic residues (plus secondary sites) completely abolished processing. Expression in furin-deficient LoVo cells; alpha1-PDX inhibitor treatment; in vitro digestion with purified furin; site-directed mutagenesis of RQRR cleavage site Proceedings of the National Academy of Sciences of the United States of America High 9653148
1998 BMP-4 is proteolytically activated by furin (and/or PC6B) during vertebrate embryogenesis. In Xenopus embryos, ectopic expression of alpha1-PDX (furin inhibitor) phenocopied BMP-4 blockade (dorsal mesoderm induction, neural induction); this was rescued by downstream BMP-4 signaling components. alpha1-PDX prevented BMP-4 cleavage in an oocyte translation assay. In vitro digestion showed furin and PC6B can cleave BMP-4 and are sensitive to alpha1-PDX. Xenopus embryo microinjection; oocyte translation assay; in vitro digestion assay; epistasis by downstream pathway rescue The EMBO journal High 9707432
2001 Furin is the primary endogenous TGF-beta1-converting enzyme. Among PC family members, furin most satisfies requirements for physiological TGF-beta1 maturation: alpha1-PDX (furin inhibitor) blocked ~80% of TGF-beta1 processing by endogenous enzymes in an in vitro digestion assay; genetic complementation of furin-deficient LoVo cells with wild-type furin gene restored production of mature, bioactivatable TGF-beta1. In vitro digestion assay with alpha1-PDX inhibitor; genetic complementation of furin-deficient LoVo cells; bioactivity assay for mature TGF-beta1 The American journal of pathology High 11141505
2001 TGF-beta1 transcriptionally upregulates its own convertase furin via the fur P1 promoter through Smad2/Smad4 signaling. Smad2 and Smad4 (possibly in complex with FAST-1) drive constitutive and TGF-beta1-inducible transactivation of the P1 promoter; dominant-negative Smad2(3SA) and Smad7 inhibited this activation; overexpression of Smad2/Smad4 enhanced P1 transactivation. Promoter-luciferase reporter cotransfection with dominant-negative Smads (Smad2-3SA, Smad7) and overexpression constructs in HepG2 cells; deletion analysis Journal of cellular physiology Medium 11424093
2002 Furin proteolytically cleaves extracellular superoxide dismutase (EC-SOD) in the polybasic heparin-binding region intracellularly (after passage through the Golgi but before secretion) at Arg213; mutation of Arg213 renders EC-SOD resistant to furin processing. Furin cleavage followed by a carboxypeptidase removes the heparin-binding region, determining EC-SOD tissue distribution and half-life. Furin overexpression in mammalian cells; specific protease inhibitors; in vitro furin digestion of purified EC-SOD; Arg213 site-directed mutation; intracellular localization by secretory pathway inhibitors The Journal of biological chemistry High 11861638
2003 Furin is required for proteolytic processing of the Semliki Forest virus (SFV) p62 envelope protein precursor to E2. In furin-deficient FD11 cells, p62 was not cleaved; transfection with human furin restored cleavage. Purified furin cleaved p62 in vitro without prior low-pH exposure. Processing controls the pH threshold for membrane fusion: unprocessed wt/p62 virus required lower pH than processed virus to trigger fusion. Mutation of the furin recognition motif in p62 (mutant L) additionally impaired virus-cell binding beyond effects on fusion. Furin-deficient CHO (FD11) cells; reconstitution by furin transfection; in vitro cleavage with purified furin; site-directed mutagenesis of furin cleavage motif; fusion and infectivity assays Journal of virology High 12584323
2004 Crystal structures of the catalytic core domain of furin were determined, providing atomic-level insight into substrate specificity and catalytic mechanism of the proprotein convertase. The structures reveal how furin recognizes polybasic substrates and inform understanding of the mechanism of serine protease catalysis by this family. X-ray crystallography of furin catalytic core domain Trends in biochemical sciences Medium 15102434
2006 Furin performs the first cleavage of RPTPkappa (a receptor tyrosine phosphatase) in the secretory pathway; subsequent ADAM10-mediated ectodomain shedding and gamma-secretase-dependent intramembrane proteolysis release the intracellular phosphatase domain (PIC), which translocates to the nucleus and dephosphorylates beta-catenin, activating beta-catenin transcriptional activity. Pharmacological inhibitors; co-immunoprecipitation; nuclear fractionation; leptomycin B nuclear export inhibition; PIC phosphatase activity assay; beta-catenin reporter assay; furin inhibitor treatment Molecular and cellular biology Medium 16648485
2006 Pro-ADAMTS9 is processed by furin at the cell surface, not intracellularly in the TGN. Pulse-chase analysis showed intact zymogen was secreted before processing. Furin-deficient cells failed to process pro-ADAMTS9; complementation with furin restored cleavage. siRNA-mediated furin knockdown reduced ADAMTS9 processing. PC5A could also process pro-ADAMTS9 but similarly processed forms were absent intracellularly. Pulse-chase analysis; furin-deficient cell lines; furin transfection rescue; PC inhibitors; furin siRNA knockdown The Journal of biological chemistry High 16537537
2008 Cripto (a GPI-anchored proteoglycan) binds both the Nodal precursor and the proprotein convertases Furin and PACE4, directing Nodal processing to the cell surface rather than the TGN/endosomal system. Cripto-Nodal association occurs during secretion; brefeldin A blocked secretion but not Cripto/Nodal export to the cell surface, indicating exposure to extracellular convertases before the TGN. Cripto guides Nodal in detergent-resistant membranes to endocytic microdomains; a Cripto-interacting region in the Nodal propeptide potentiated effects of proteolytic maturation on signaling. Co-immunoprecipitation of Cripto with Furin/PACE4 and Nodal; brefeldin A treatment; density gradient fractionation; antibody uptake; GFP-Flotillin marker; signaling readout The EMBO journal High 18772886
2010 Furin processes CD109 in the Golgi apparatus, cleaving the 205 kDa precursor at the RRRR motif (Arg1273) into 180 kDa and 25 kDa fragments. Mutation R1273S abolishes cleavage, and the uncleaved CD109-R1273S neither associates with the type I TGF-beta receptor nor significantly regulates TGF-beta signaling, whereas the processed 180/25 kDa CD109 complex associates with TGF-beta RI and suppresses TGF-beta signaling. Site-directed mutagenesis of furin cleavage site (RRRR→RRRSER); co-immunoprecipitation of CD109 with TGF-beta RI; cell growth and TGF-beta signaling assays Oncogene High 20101215
2010 In hepatocytes, furin is the major in vivo inactivating protease of circulating PCSK9, cleaving it at Arg218 to generate a ~55 kDa inactive form. Hepatocyte-specific furin knockout (Fur-hKO) mice showed strongly reduced PCSK9 inactivated form in plasma and ~26% drop in LDL receptor protein in liver, with ~35% increase in PCSK9 mRNA and loss of PCSK9 cleavage. Only full-length, membrane-bound furin (not soluble furin) in primary hepatocytes performed this cleavage. Hepatocyte-specific conditional furin knockout mice; plasma PCSK9 cleavage analysis; LDL receptor protein quantification; furin overexpression in primary hepatocytes; human heterozygote mutant analysis The Journal of biological chemistry High 21147780
2012 Furin is required in endothelial cells for cardiac development: endothelial-specific furin knockout (ecKO) mice die postnatally and exhibit ventricular septal defects and valve malformations. Furin-deficient endothelial cells cannot proliferate, rescued by extracellular soluble furin. Endothelin-1 (ET-1), adrenomedullin (Adm), and TGF-beta1—but not BMP4—were confirmed as in vivo endothelial furin substrates (mature ET-1 and BMP4 reduced ~90% in ecKO endothelial cells). Endothelial cell-specific Furin conditional knockout (Cre-lox); MRI of embryos; primary endothelial cell cultures; soluble furin rescue; substrate processing analysis (ET-1, Adm, TGF-beta1, BMP4) Molecular and cellular biology High 22733989
2013 Furin is required for trophoblast syncytialization. Furin is highly expressed in syncytial trophoblast; its expression is lower in pre-eclamptic placentas. Furin-specific siRNA or inhibitors blocked cytotrophoblast cell fusion in BeWo cells and human placental explants. IGF1R is a furin substrate whose processing is an essential mechanism for syncytialization. Lentivirus-mediated furin RNAi targeting mouse trophectoderm disrupted syncytiotrophoblast development and embryogenesis. siRNA knockdown; furin inhibitor treatment; BeWo cell fusion assay; primary cytotrophoblast and placental explant cultures; lentivirus-mediated RNAi in mouse trophectoderm; IGF1R processing analysis Cell death & disease High 23598405
2013 PCSK3/furin directly cleaves proapelin to generate apelin-13, without producing longer isoforms (apelin-36 or longer forms), in vitro. Neither PCSK1 nor PCSK7 showed appreciable proapelin cleavage activity. Both proapelin and PCSK3 transcript levels are increased in adipose tissue with obesity and during adipogenesis. In vitro cleavage assay of proapelin with purified PCSK3, PCSK1, and PCSK7; transcript expression analysis in adipose tissue FEBS open bio Medium 24251091
2014 Furin is the major proprotein convertase required for processing of KISS1 into kisspeptins. shRNA-mediated knockdown of furin (but not PCSK5 or PCSK7) blocked KISS1 processing. PC inhibitors (Dec-RVKR-CMK and alpha1-PDX) completely inhibited KISS1 processing in KISS1-overexpressing cells. shRNA knockdown of furin, PCSK5, and PCSK7; PC inhibitor treatment (Dec-RVKR-CMK, alpha1-PDX); KISS1 processing assay PloS one Medium 24454770
2015 Crystal structure of human furin in complex with the peptidomimetic inhibitor MI-1148 (Ki = 5.5 pM) was determined, revealing that the N-terminal guanidinomethyl group in the para-position of the P5 phenyl ring occupies the same binding pocket as in structurally related inhibitors, defining key P5 interactions. MI-1148 also strongly inhibits PC1/3 but less so PC2. X-ray crystallography (co-crystal structure of furin with inhibitor MI-1148); enzyme inhibition assays (Ki determination); cell-based antiviral/antibacterial assays ChemMedChem High 25974265
2015 PC7, Furin, and Pace4 jointly regulate E-cadherin processing during morula compaction in blastocyst formation; their combined activity modulates cell-cell adhesion required for ICM specification via Hippo/YAP signaling. Live imaging of a transgenic reporter substrate demonstrated differential PC activity in inner vs. outer cells in partially nonoverlapping compartments. PC7/Furin/Pace4 mutant embryos; furin inhibitor; live imaging of transgenic reporter substrate; E-cadherin processing analysis The Journal of cell biology Medium 26416966
2016 Furin-deficient myeloid cells exhibit elevated pro-inflammatory cytokine production and altered macrophage polarization. LysMCre-fur(fl/fl) mice had elevated serum IL-1beta, reduced splenocyte numbers, and accelerated LPS-induced mortality with elevated pro-inflammatory cytokines. Furin inhibited Nos2 and promoted Arg1 expression (M1/M2 balance). Furin was required for normal bioactive TGF-beta1 production but inhibited maturation of TACE and Caspase-1 in myeloid cells. Conditional myeloid furin knockout (LysMCre-fur(fl/fl)); LPS challenge model; serum cytokine quantification; genome-wide gene expression analysis; macrophage polarization markers Oncotarget Medium 27527873
2018 PCSK3/furin promotes intracellular cleavage of lipoprotein lipase (LPL) in adipocytes, and ANGPTL4 promotes this PCSK-mediated LPL cleavage. Pcsk3/furin silencing significantly decreased LPL cleavage in 3T3-L1 adipocytes; Angptl4 silencing diminished PCSK-mediated LPL cleavage; stimulation of ANGPTL4 by fasting enhanced furin-dependent LPL cleavage. The cleavage occurs intracellularly. siRNA silencing of Pcsk3/furin and Angptl4 in 3T3-L1 adipocytes; PCSK inhibitor (decanoyl-RVKR-CMK); Angptl4-/- mice; heparin-treatment to distinguish intracellular vs. surface LPL The Journal of biological chemistry Medium 30021841
2018 PCSK3 (furin), PCSK5, and PCSK6 can all cleave GDF15 precursor to generate mature GDF15, both in vitro (in cardiomyocytes) and in vivo (in mouse hearts). These three PCSKs mediate a crucial step of GDF15 maturation through proteolytic cleavage. In vitro cleavage assays; overexpression of PCSK family members in cardiomyocytes; in vivo mouse heart analysis Molecular and cellular biology Medium 30104250
2019 Furin inhibition (with alpha1-PDX) reduces atherosclerotic lesion area and vascular remodeling in Ldlr-/- and Apoe-/- mice. MMP2, a furin substrate, was significantly reduced in the aorta of inhibitor-treated mice. Furin overexpression in the wire-injury model caused a 67% increase in intimal plaque thickness, directly correlating furin levels with atherosclerosis. In vitro, furin inhibition reduced monocyte migration and macrophage/endothelial inflammatory gene expression. In vivo alpha1-PDX inhibitor administration in Ldlr-/- and Apoe-/- mice; wire-injury carotid model with furin overexpression; MMP2 substrate processing analysis; in vitro monocyte migration and cytokine assays Arteriosclerosis, thrombosis, and vascular biology Medium 30651003
2021 The furin cleavage site (PRRAR) in SARS-CoV-2 spike protein is critical for efficient replication in human respiratory cells and pathogenesis in vivo. Deletion of the furin site (ΔPRRA) reduced spike protein processing, impaired replication in Calu-3 human respiratory cells, and attenuated disease in hamster and K18-hACE2 transgenic mouse models. Despite attenuation, ΔPRRA mutant conferred protection against parental virus rechallenge. SARS-CoV-2 reverse genetics (furin site deletion mutant ΔPRRA); cell-based replication kinetics; hamster and transgenic mouse pathogenesis models; spike protein processing analysis; neutralization assays Nature High 33494095
2022 Furin cleaves the SARS-CoV-2 spike protein at both S1/S2 (PRA685↓) and S2' (KPS815↓) sites. The S2' cleavage site was identified by proteomics for the first time, and its cleavage was strongly enhanced by ACE2 engagement with S protein. Novel furin inhibitors (BOS) blocked processing at both sites in HeLa cells. Combined furin (BOS) and TMPRSS2 (camostat) inhibition achieved ~95% reduction of SARS-CoV-2 infection of Calu-3 lung cells. TMPRSS2-mediated ACE2 shedding was required for TMPRSS2-dependent enhancement of fusion in the absence of S1/S2 priming; the collectrin dimerization domain of ACE2 was essential for TMPRSS2 effect on fusion. Proteomics identification of S2' cleavage site; pharmacological furin inhibitors (BOS); combined inhibitor assays; quantitative cell-to-cell fusion assays; SARS-CoV-2 infection of Calu-3 cells Journal of virology High 35343766
2010 Osteopontin (OPN) induces furin expression in cervical cancer cells via CD44-mediated activation of MKK3/6→p38→NF-kB signaling cascade. NF-kB-dependent transcription drives furin expression, which in turn enhances cell motility and HPV processing. Blockades of MKK3/6, p38alpha/beta, NF-kB, or furin all reduced OPN-induced cell motility and tumor growth in a xenograft model. Pharmacological inhibitors of MKK3/6, p38, NF-kB; furin expression analysis; cell motility assays; mouse xenograft model with OPN overexpression/shRNA knockdown; furin overexpression Cancer research Medium 20980434
2005 CDX2 transcription factor binds to the CBS2 sequence (nt -1827 to -1821) of the furin P1 promoter and activates furin expression during intestinal epithelial cell differentiation. CDX2-driven furin expression correlates with enterocyte differentiation; furin inhibition blocked lactase-phlorizin hydrolase activity and strongly attenuated epithelial polarity and brush-border formation. EMSA and supershift assays; site-specific mutagenesis of CDX2 binding site; chromatin immunoprecipitation; luciferase reporter assays; in situ hybridization; furin inhibitor treatment of Caco-2/15 cells American journal of physiology. Gastrointestinal and liver physiology High 16239403
2012 Furin activates N-cadherin by cleaving its prosegment at RQKR↓DW161 (releasing an ~17 kDa prosegment), while PC5A inactivates NCAD by cleaving at a second site RIRSDR↓DK189 (releasing an ~20 kDa product that abolishes Trp161-dependent adhesion). In invasive glioma cells, furin and PC5A levels are inversely correlated; cell-surface expression of unprocessed proNCAD or PC5A-cleaved NCAD reduces cell-cell adhesion and increases migration. Analysis of NCAD processing in human glioma cell lines with different Furin/PC5A expression levels; furin-null vs. PC5A-expressing cells; prosegment size analysis; cell adhesion and migration assays Neoplasia Medium 23097623
2018 Furin overexpression in transgenic mice increases dendritic spine density, enhances LTP and spatial memory, and elevates the ratio of mature BDNF to pro-BDNF in cortex and hippocampus along with increased ERK and CREB activity. Hippocampal CREB knockdown diminished LTP and cognitive facilitation in Furin-Tg mice, placing furin upstream of BDNF-ERK-CREB signaling in neuronal plasticity. Furin transgenic mice; dendritic spine counting; LTP electrophysiology; Morris water maze; BDNF processing (mature vs. pro); ERK and CREB phosphorylation; lentiviral CREB knockdown Cellular and molecular life sciences Medium 29302702
2018 Placenta-specific 1 (Plac1) activates furin at the oocyte membrane during the germinal vesicle stage; active furin then activates IGF-1 receptor (IGF-1R) to maintain microvillus organization. Upon meiosis onset, active furin/IGF-1R complex relocates to cytoplasm and activates (phosphorylates) Akt to promote meiosis. Plac1 knockdown disrupted microvillus organization, reduced oocyte maturation, increased aneuploidy, and disrupted fertilization. Plac1 knockdown in mouse oocytes; immunoprecipitation-MALDI mass spectrometry; furin activity assay; IGF-1R processing and phospho-Akt analysis; live-cell localization imaging FASEB journal Medium 29723063
2018 Furin transgenic overexpression increases epileptic susceptibility; furin knockdown restrained epileptic activity. Furin influences neuronal inhibitory synaptic transmission by regulating postsynaptic GABA-A receptor (GABAAR) beta2/3 surface and total protein expression through changes in GABAAR beta2/3 transcription levels (not protein degradation). Furin transgenic and lentiviral knockdown mice; whole-cell patch clamp; Western blot for GABAAR beta2/3 membrane vs. total protein; transcription level analysis; epilepsy susceptibility behavioral assay Cell death & disease Medium 30333479

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nature reviews. Molecular cell biology 993 12360192
2022 DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife 757 35029144
1998 The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proceedings of the National Academy of Sciences of the United States of America 591 9653148
2021 Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature 590 33494095
2013 Transcriptional regulation by Ferric Uptake Regulator (Fur) in pathogenic bacteria. Frontiers in cellular and infection microbiology 378 24106689
1999 Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends in cell biology 361 10087614
2007 Functional specialization within the Fur family of metalloregulators. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 333 17216355
1999 OxyR and SoxRS regulation of fur. Journal of bacteriology 312 10419964
1990 Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Molecular biology reports 246 2094803
2019 Furin-mediated protein processing in infectious diseases and cancer. Clinical & translational immunology 243 31406574
2015 Rising to the challenge: accelerated pace of discovery transforms marine virology. Nature reviews. Microbiology 230 25639680
2002 Recognition of DNA by Fur: a reinterpretation of the Fur box consensus sequence. Journal of bacteriology 227 12374814
2001 Evidence that furin is an authentic transforming growth factor-beta1-converting enzyme. The American journal of pathology 213 11141505
1998 BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development. The EMBO journal 191 9707432
1995 Furin-induced cleavage and activation of Shiga toxin. The Journal of biological chemistry 173 7738018
2005 Iron and fur regulation in Vibrio cholerae and the role of fur in virulence. Infection and immunity 161 16299312
2022 Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity. Journal of virology 144 35343766
1991 Identification and cloning of a fur regulatory gene in Yersinia pestis. Journal of bacteriology 135 1898928
2018 Accelerating the Pace of Chemical Risk Assessment. Chemical research in toxicology 134 29600706
1991 Structural dynamics and functional domains of the fur protein. Biochemistry 126 1868094
2010 In vivo evidence that furin from hepatocytes inactivates PCSK9. The Journal of biological chemistry 124 21147780
2019 The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases. Viruses 119 31505793
2020 Furin Cleavage Site Is Key to SARS-CoV-2 Pathogenesis. bioRxiv : the preprint server for biology 118 32869021
2017 The proprotein convertase furin in tumour progression. International journal of cancer 116 28369813
2012 Structure and regulon of Campylobacter jejuni ferric uptake regulator Fur define apo-Fur regulation. Proceedings of the National Academy of Sciences of the United States of America 115 22665794
1993 PACE/furin can process the vitamin K-dependent pro-factor IX precursor within the secretory pathway. The Journal of biological chemistry 102 8473289
2006 Histone deacetylase inhibitors: gathering pace. Current opinion in pharmacology 101 16781195
2006 Furin-, ADAM 10-, and gamma-secretase-mediated cleavage of a receptor tyrosine phosphatase and regulation of beta-catenin's transcriptional activity. Molecular and cellular biology 95 16648485
2003 Furin processing and proteolytic activation of Semliki Forest virus. Journal of virology 85 12584323
2002 Evolution of colorectal cancer: change of pace and change of direction. Journal of gastroenterology and hepatology 75 11987262
2010 p38 kinase is crucial for osteopontin-induced furin expression that supports cervical cancer progression. Cancer research 74 20980434
2020 Furin cleavage sites naturally occur in coronaviruses. Stem cell research 71 33340798
2015 Therapeutic uses of furin and its inhibitors: a patent review. Expert opinion on therapeutic patents 71 25563687
2013 Preferential apelin-13 production by the proprotein convertase PCSK3 is implicated in obesity. FEBS open bio 70 24251091
2008 Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation. The EMBO journal 69 18772886
2000 The proprotein convertases furin and PACE4 play a significant role in tumor progression. Molecular carcinogenesis 69 10900462
2014 Coordination of plant mitochondrial biogenesis: keeping pace with cellular requirements. Frontiers in plant science 68 24409193
2010 Processing of CD109 by furin and its role in the regulation of TGF-beta signaling. Oncogene 68 20101215
2017 Ferric Uptake Regulator Fur Is Conditionally Essential in Pseudomonas aeruginosa. Journal of bacteriology 67 28847923
2004 The kindest cuts of all: crystal structures of Kex2 and furin reveal secrets of precursor processing. Trends in biochemical sciences 67 15102434
1992 Fur regulation in Yersinia species. Molecular microbiology 67 1406286
2017 Redox Sensing by Fe2+ in Bacterial Fur Family Metalloregulators. Antioxidants & redox signaling 65 28938859
2018 Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes. The Journal of biological chemistry 63 30021841
2015 Novel Furin Inhibitors with Potent Anti-infectious Activity. ChemMedChem 63 25974265
1996 Furin/PACE/SPC1: a convertase involved in exocytic and endocytic processing of precursor proteins. FEBS letters 62 8635573
2019 FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice. Arteriosclerosis, thrombosis, and vascular biology 59 30651003
1994 Cloning and sequencing of the Legionella pneumophila fur gene. Gene 59 8200525
2002 Furin proteolytically processes the heparin-binding region of extracellular superoxide dismutase. The Journal of biological chemistry 58 11861638
1994 Expression of the dibasic proprotein processing enzyme furin is directed by multiple promoters. The Journal of biological chemistry 57 8132667
2006 Cell-surface processing of pro-ADAMTS9 by furin. The Journal of biological chemistry 56 16537537
2022 The emerging role of furin in neurodegenerative and neuropsychiatric diseases. Translational neurodegeneration 55 35996194
2022 The proprotein convertase furin in cancer: more than an oncogene. Oncogene 54 34997216
2009 Transcriptomic response of Listeria monocytogenes to iron limitation and Fur mutation. Applied and environmental microbiology 54 19933349
2010 Light forces the pace: optical manipulation for biophotonics. Journal of biomedical optics 51 20799781
1998 Cloning and characterization of the fur gene from Helicobacter pylori. FEMS microbiology letters 50 9503612
2018 Growth Differentiation Factor 15 Maturation Requires Proteolytic Cleavage by PCSK3, -5, and -6. Molecular and cellular biology 49 30104250
2015 Impact of Anaerobiosis on Expression of the Iron-Responsive Fur and RyhB Regulons. mBio 49 26670385
1996 Isolation and analysis of a fur mutant of Neisseria gonorrhoeae. Journal of bacteriology 49 8763952
2001 Involvement of Smads in TGFbeta1-induced furin (fur) transcription. Journal of cellular physiology 47 11424093
2010 Associations between genetic variations in the FURIN gene and hypertension. BMC medical genetics 45 20707915
1999 Processing and routage of HIV glycoproteins by furin to the cell surface. Virus research 45 10225274
2021 Why All the Fury over Furin? Journal of medicinal chemistry 44 34340303
2017 Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets. Atherosclerosis 43 28400053
2012 Loss of endothelial furin leads to cardiac malformation and early postnatal death. Molecular and cellular biology 42 22733989
2005 Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels. Journal of molecular medicine (Berlin, Germany) 42 16244876
2016 Furin Cleavage of L2 during Papillomavirus Infection: Minimal Dependence on Cyclophilins. Journal of virology 41 27122588
2003 A novel DNA-binding site for the ferric uptake regulator (Fur) protein from Bradyrhizobium japonicum. The Journal of biological chemistry 40 12881516
2003 Regulation of fur expression by RpoS and fur in Vibrio vulnificus. Journal of bacteriology 39 13129962
2013 The proprotein convertase furin is required for trophoblast syncytialization. Cell death & disease 37 23598405
2016 Myeloid cell expressed proprotein convertase FURIN attenuates inflammation. Oncotarget 36 27527873
2023 Meddling with Metal Sensors: Fur-Family Proteins as Signaling Hubs. Journal of bacteriology 35 37010421
1999 Characterization of the Acinetobacter baumannii Fur regulator: cloning and sequencing of the fur homolog gene. FEMS microbiology letters 35 9919669
2010 Selective and potent furin inhibitors protect cells from anthrax without significant toxicity. The international journal of biochemistry & cell biology 34 20197107
2005 The CDX2 transcription factor regulates furin expression during intestinal epithelial cell differentiation. American journal of physiology. Gastrointestinal and liver physiology 34 16239403
2000 Characterization and mutagenesis of fur gene from Burkholderia pseudomallei. Gene 33 10974543
2018 Independent and cooperative regulation of staphylopine biosynthesis and trafficking by Fur and Zur. Molecular microbiology 32 29431891
1997 The fur gene from Klebsiella pneumoniae: characterization, genomic organization and phylogenetic analysis. Gene 32 9055816
2017 Optimization of Substrate-Analogue Furin Inhibitors. ChemMedChem 31 29059503
2015 Association of FURIN and ZPR1 polymorphisms with metabolic syndrome. Biomedical reports 31 26405538
2023 Ferric uptake regulator (Fur) binds a [2Fe-2S] cluster to regulate intracellular iron homeostasis in Escherichia coli. The Journal of biological chemistry 30 37100285
2004 Cross-inhibition between furin and lethal factor inhibitors. Biochemical and biophysical research communications 30 15358148
2012 Generation and characterization of non-competitive furin-inhibiting nanobodies. The Biochemical journal 29 22920187
2008 Expression of PCSK1 (PC1/3), PCSK2 (PC2) and PCSK3 (furin) in mouse small intestine. Regulatory peptides 29 18706454
2016 Quaternary Structure of Fur Proteins, a New Subfamily of Tetrameric Proteins. Biochemistry 28 26886069
2016 Characterization of the Neisseria gonorrhoeae Iron and Fur Regulatory Network. Journal of bacteriology 27 27246574
2015 Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors. PloS one 27 26110264
2019 Near-Infrared Fluorescent Furin Probe for Revealing the Role of Furin in Cellular Carcinogenesis and Specific Cancer Imaging. Analytical chemistry 26 31282656
2020 Phage-Assisted Continuous Evolution (PACE): A Guide Focused on Evolving Protein-DNA Interactions. ACS omega 22 33134656
2012 Opposite roles of furin and PC5A in N-cadherin processing. Neoplasia (New York, N.Y.) 22 23097623
2018 Keeping PACE with Ph Positive to Ph-Like Detection in B-Lineage Acute Lymphoblastic Leukemia: A Practical and Cost Effective (PACE) Approach in a Resource Constrained Setting. Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion 21 30369727
2014 Effect of Furin inhibitor on lung adenocarcinoma cell growth and metastasis. Cancer cell international 21 24876827
2024 CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny. Cell reports 20 39352808
2019 New insights into the tetrameric family of the Fur metalloregulators. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 20 31165314
2017 Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin. ChemMedChem 20 28334511
2018 Transgenic overexpression of furin increases epileptic susceptibility. Cell death & disease 19 30333479
2015 PC7 and the related proteases Furin and Pace4 regulate E-cadherin function during blastocyst formation. The Journal of cell biology 19 26416966
2014 Furin is the major proprotein convertase required for KISS1-to-Kisspeptin processing. PloS one 19 24454770
2010 Blockade of furin activity and furin-induced tumor cells malignant phenotypes by the chemically synthesized human furin prodomain. Current medicinal chemistry 19 20459383
2018 Furin promotes dendritic morphogenesis and learning and memory in transgenic mice. Cellular and molecular life sciences : CMLS 18 29302702
2018 Placenta-specific 1 regulates oocyte meiosis and fertilization through furin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 29723063

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