Disease relevance of Pcsk3

• We have identified two rat insulinoma cDNAs that code for proteins homologous to the Kex2 dibasic protease of yeast and the mammalian furin gene product [1].
• To further define the role of each convertase, and particularly PC1 and PC2, in pro-TRH processing, recombinant vaccinia viruses were used to coexpress the prohormone convertases PC1, PC2, PACE4, PC5-B, furin, or control dynorphin together with rat prepro-TRH in constitutively secreting LoVo cells or in the regulated endocrine GH4C1 cell line [2].
• Hence, we propose that BDV GP-84 is involved in attachment to the cell surface receptor whereas its furin-cleaved product, GP-43, is involved in pH-dependent fusion after internalization of the virion by endocytosis [3].
• We therefore compared the specificity of furin with those of proteases in a variety of cultured cells and in a rat Golgi fraction, using the HA cleavage mutants of a virulent avian influenza virus, A/Turkey/Ireland/1378/85 (H5N8) [4].
• Processing of the Borna disease virus glycoprotein gp94 by the subtilisin-like endoprotease furin [5].

High impact information on Pcsk3

• Interaction of furin in immature secretory granules from neuroendocrine cells with the AP-1 adaptor complex is modulated by casein kinase II phosphorylation [6].
• Interaction between AP-1 and furin is dependent on phosphorylation of the enzyme's cytoplasmic domain by casein kinase II [6].
• The cytoplasmic domain mediates localization of furin to the trans-Golgi network en route to the endosomal/lysosomal system [7].
• To investigate the mechanisms of membrane protein localization to the Golgi complex, we have examined the intracellular trafficking of epitope-tagged forms of the mammalian endopeptidase, furin, in stably transformed rat basophilic leukemia cells [7].
• Interestingly, deletion of most of the cytoplasmic domain of furin results in a molecule that is predominantly localized to intracellular vesicles, some of which display characteristics of lysosomes [7].

Biological context of Pcsk3

• In the primitive streak stage of embryogenesis (e7) furin is expressed in both endoderm and mesoderm [8].
• The amino acid sequence homologies among rat, human, and mouse PC1, PC2, and furin are consistent with each being a highly conserved but distinct member of a larger family of mammalian subtilisin-like proteases [9].
• The expression of furin in pancreatic beta-cells induces faster cell growth and a decrease in differentiated beta-cell-specific characteristics [10].
• H-500 Leydig tumor cells were stably transfected with a mammalian expression plasmid containing furin cDNA in an anti-sense orientation [11].
• Our results revealed a parallel upregulation of furin, PC5, and PC7 in PCNA-immunolabeled cells [12].

Anatomical context of Pcsk3

• Brefeldin A (BFA), a Golgi-disturbing agent, inhibited MT1-MMP activation, indicating that it occurs in the trans-Golgi network (TGN), where furin is concentrated and colocalized with MT1-MMP [13].
• Furthermore, inhibition of furin attenuated TGF-beta1-enhanced migration on gelatin-coated membranes (p<0.05) [13].
• We found that in the absence of furin (LoVo cells) or CHO cells treated with BFA, only one moiety was observed, and that corresponds to the same electrophorectic mobility to the GHRH precursor [14].
• Furin is shuttled to the cell surface through the trans-Golgi network and endosomal system, and its only known role on plasma membrane consists in activation of opportunistic pathogenic entities [15].
• Furin interacts with proMT1-MMP and integrin alphaV at specialized domains of renal cell plasma membrane [15].

Associations of Pcsk3 with chemical compounds

• Inhibition of furin inhibited angiotensin II-induced TGF-beta1 activation, indicating that TGF-beta1 amplifies its activating convertase in CFBs [13].
• The PCs furin and PC7, which display a comparable subcellular localization and cleavage activity, were found in VSMCs, but their levels did not increase following PDGF-BB, Ang II, or FCS stimulation [16].
• Furin expression continued, however, even after the BrdU incorporation decreased [10].
• After overloading Golgi-derived vesicles with very-low-density lipoproteins (VLDL) by feeding rats with ethanol, the distribution of PC7/LPC was shifted markedly towards lower densities, in contrast with those of furin and the TGN marker [17].
• To test whether known processing enzymes can perform this cleavage, purified proCPE was incubated with furin, prohormone convertase 1, or a dynorphin converting enzyme, and the products were analyzed on denaturing polyacrylamide gels [18].

Co-localisations of Pcsk3

• Double immunogold labelings indicate that furin colocalizes with the caveolae/raft-marker caveolin-1 in the Golgi apparatus and in the basolateral endosomes [19].

Regulatory relationships of Pcsk3

• METHODS AND RESULTS: Stimulation of CFBs from adult Sprague-Dawley rats with TGF-beta1 (20 ng/ml) induced furin, but had no effect on the closely related PC5 [13].
• Both membrane type-1 MMP (MT1-MMP) and the integrin alphaV subunit are fully activated upon cleavage at a furin recognition site [15].
• It is concluded that in the immature secretory granules of Chief cells, furin activates proprotein convertase 7 that, in turn, cleaves the extracellular portion of membrane-bound leptin receptors [20].

Other interactions of Pcsk3

• The IGF-1 receptor (IGF-1R) and MT1-MMP are synthesized as larger precursor proproteins, which require endoproteolytic activation by the proprotein convertases (PCs) furin/PC5 to gain full biological activity [21].
• Stepwise posttranslational processing of progrowth hormone-releasing hormone (proGHRH) polypeptide by furin and PC1 [14].
• Colocalization studies demonstrated that furin is expressed in the parathyroid, whereas proprotein convertase (PC)1 and PC2 are not [22].
• Furin and PC6 were weakly and evenly expressed in the entire islet [23].
• These results suggest the involvement of furin in the ConA-induced activations of MT1-MMP and MMP-2 [24].

Analytical, diagnostic and therapeutic context of Pcsk3

• By using in vivo gene delivery, western blotting and immunogold electron microscopy, we provide evidence of significant pools of furin and proMT1-MMP along the surface of cells lining basement membranes [15].
• In addition, furin mRNAs were detected predominantly in differentiated epithelial cells of the villus, as determined by in situ hybridization [25].
• Electrophoretic mobility shift/supershift assays followed by site-specific mutagenesis and chromatin immunoprecipitation identified the CDX DNA-binding site (CBS)2 sequence from nt -1827 to -1821 as the major CBS involved in furin P1 promoter activation [25].
• Northern blot analysis of RNA extracted from cardiac tissues showed high levels of furin and PACE4 mRNA in the atria and ventricles, while PC5 mRNA was found to be expressed at high levels in the dorsal aorta [26].
• Using in vivo gene delivery, together with high-resolution immunogold electron microscopy, we were able to assign precise subcellular locations to furin [19].

References