Furin is a proprotein convertase that activates a variety of regulatory proteins in the constitutive exocytic and endocytic pathway (Louagie et al., 2008).

Roebroek et al. (1986) described DNA sequences in the immediate upstream region from the FES oncogene (190030). They designated this FUR (for FES upstream region) and showed that in both man and cat the sequence codes for a 4.5-kb mRNA. The nucleotide sequence of a 3.1-kb FUR-specific cDNA isolated from a human cDNA library showed an open reading frame of 1,498 bp from which the 499 carboxy-terminal amino acids of the primary FUR translation product could be deduced. Computer analysis indicated that this product, called furin, contained a possible transmembrane domain resembling that of class II MHC antigens. Roebroek et al. (1986) concluded that FUR may encode a membrane-associated protein with a recognition function.

Studying its expression by Northern blot analysis using poly(A)-selected RNA from a variety of organs, Schalken et al. (1987) found that the FUR gene is differentially expressed, being high in organs such as liver and kidney and very low in others such as heart muscle, lung, and testis. FUR expression discriminated sharply between small cell lung cancers, which had no expression, and nonsmall cell lung cancers, which had strong elevation of expression.

The FUR gene is located approximately 1 kb upstream of the FES gene on chromosome 15q25-q26 (Roebroek et al., 1986). The 2 genes are transcribed in the same direction.

Seidah et al. (1991) assigned the homologous gene (Pcsk3) to mouse chromosome 7 by in situ hybridization. Copeland et al. (1992) refined the regional localization on mouse chromosome 7. There is other evidence of conservation of synteny between human chromosome 15 and mouse chromosome 7.

Mbikay et al. (1995) showed that another member of the family of proprotein convertases, PACE4 (167405), is encoded by the Pcsk6 locus, which maps to mouse chromosome 7 at a distance of 13 cM from the Pcsk3 locus. This finding was in concordance with the known close proximity of these 2 loci in the homologous region on human chromosome 15q25-qter.

Hendy et al. (1995) reported experiments strongly suggesting that furin is the enzyme responsible for the physiologic processing of proparathyroid hormone to PTH (168450).

Dubois et al. (1995) demonstrated in vitro that pro-TGFB1 (see 190180) was cleaved by furin to produce a biologically active TGFB1 protein. Expression of pro-TGFB1 in furin-deficient cells produced no TGFB1, while coexpression of pro-TGFB1 and furin led to processing of the precursor.

Blanchette et al. (1997) showed that furin mRNA levels were increased in rat synovial cells by the addition of TGFB1. This effect was eliminated by pretreatment with actinomycin-D, suggesting to them that regulation was at the gene transcriptional level. Treatment of rat synoviocytes and kidney fibroblasts with TGFB1 or TGFB2 resulted in increased pro-TGFB1 processing, as evidenced by the appearance of a 40-kD immunoreactive band corresponding to the TGFB1 amino-terminal pro-region. Treatment of these cells with TGFB2 resulted in a significant increase in extracellular mature TGFB1. Blanchette et al. (1997) concluded that TGFB1 upregulates gene expression of its own converting enzyme.

Pesu et al. (2008) demonstrated that conditional deletion of furin in T cells allowed for normal T-cell development but impaired the function of regulatory and effector T cells, which produced less TGFB1. Furin-deficient regulatory T cells were less protective in a T-cell transfer colitis model and failed to induce FOXP3 (300392) in normal T cells. Additionally, furin-deficient effector cells were inherently overactive and were resistant to suppressive activity of wildtype T regulatory cells. Thus, Pesu et al. (2008) concluded that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its nonredundant essential functioning in regulating TGFB1 production.

Louagie et al. (2008) stated that knockout of Fur in mice is embryonic lethal. They found that pancreas-specific ablation of Fur expression resulted in mice that were born at the expected mendelian ratio and showed normal growth and fertility. Pancreatic deletion of Fur impaired insulin (INS; 176730) secretion and processing of several proproteins, including proglucagon (GCG; 138030) and proPc2 (PCSK2; 162151). Furin-deficient beta cells exhibited defects in acidification of secretory granules, suggesting that loss of Fur impaired processing of Ac45 (ATP6AP1; 300197), an accessory subunit of the proton pump vacuolar ATPase. Quantitative RT-PCR showed that Ac45 was highly expressed in islets of Langerhans, and furin cleaved Ac45 ex vivo. Knockdown of Fur or Ac45 in mouse insulinoma cells via short hairpin RNA resulted in loss of regulated secretion and impaired proinsulin II processing similar to observations in mice with pancreatic furin deletion.