Disease relevance of PCSK6

• To identify the roles of the bHLH factor and E-box elements in regulating PACE4 gene expression in neural development, we analysed the effects of human achaete-scute homologue 1 (hASH-1) on PACE4 gene expression with various neuroblastoma cell lines [1].
• In this study, the regulatory mechanism for PACE4 expression in placenta was analyzed using a human placental choriocarcinoma cell line, BeWo cells [2].
• PACE4 transcripts were detected in eight of 14 adenocarcinomas and in seven of 17 squamous cell carcinomas; they were detectable in only two of seven SCLCs [3].
• This processing defect was corrected by the expression of furin and PC6 but not of PACE4 and a control wild-type vaccinia virus [4].
• A role for PACE4 in the proteolytic activation of anthrax toxin protective antigen [5].

Psychiatry related information on PCSK6

• The test battery and questionnaire on function and physical activity were administered twice, 7-10 days apart to 38 men and 12 women aged 54-80 years at the Baltimore Veterans Affairs Medical Center. Tests included fast pace 4 and 20-meter walks, 6-minute and graded treadmill walks, and a seated step test [6].

High impact information on PCSK6

• The construct with all three sites mutated (termed proNGF123) gave all proNGF with no mature NGF and was not cleaved by three proconvertases (furin, PACE-4, and PC-2) known to proteolyze proneurotrophins in vivo [7].
• Using an animal model of human SCC progression, we provide evidence of increased PACE4 expression in SPCC cell lines and primary tumors induced by chemical carcinogenesis protocols, thus implicating this proprotein convertase in the process of tumor progression [8].
• Expression of PACE4 in chemically induced carcinomas is associated with spindle cell tumor conversion and increased invasive ability [8].
• Although convertases such as PACE4 and PC6B processed proADAMTS-1, we found that furin was the most efficient enzyme at producing the mature ADAMTS-1 87-kDa moiety [9].
• Multiple transcripts are produced for all the mammalian convertases, but only in the cases of PC4, PACE4, and PC5 does differential splicing result in the modification of the C-terminal sequence of these enzymes [10].

Biological context of PCSK6

• These results suggest that the alteration of PACE4 gene expression by hASH-1 causes rapid changes in the biological activities of TGF-beta-related proteins via post-translational modification of these proteins [1].
• Like that of furin, the tissue distribution of PACE4 is widespread [11].
• PACE4 promoter activity was measured in HeyC2 and OCC-1 cells using transiently transfected luciferase reporter plasmids [12].
• Methylation analysis of 79 CpG dinucleotides within the PACE4 promoter and exon I (-196/+340) revealed that the percentage of methylated cytosine nucleotides was 8-9% in normal OSE, but 58-93% in OC cells [12].
• The observation that established OC cell lines have reduced PACE4 expression, but maintained the ability to support PACE4 promoter activity, led to the hypothesis that reduced expression may be due to epigenetic modification of the PACE4 gene, such as DNA methylation and histone deacetylation [12].

Anatomical context of PCSK6

• The expressions of PACE4 and hASH-1 are correlated inversely in these cell lines [1].
• In contrast, PC2 transcripts were detected only in skin mast cells, whereas transcripts for paired basic amino acid converting enzyme 4 (PACE4) were present only in HMC-1 cells [13].
• We previously reported that PACE4 is highly expressed in syncytiotrophoblasts of human placenta [Tsuji et al. (2003) BIOCHIM: Biophys. Acta 1645, 95-104] [2].
• In contrast, PACE4-CS is not secreted since it remains in the endoplasmic reticulum as an inactive zymogen form, thereby emphasizing the importance of the integrity of the P-domain [14].
• PACE4 is expressed at high levels in the anterior pituitary, central nervous system, the developing olfactory bulb, heart, and liver [15].

Associations of PCSK6 with chemical compounds

• An apparent association was observed only between PACE4 and estrogen receptors [16].
• Heparin has no inhibitory activity against PACE4 [17].
• The interaction between PACE4 and heparan sulfate proteoglycans might play an important role in the delicate spatiotemporal regulation of TGFbeta-related factors' biological activity [17].
• Treatment with the demethylating agent 5-aza-2'-deoxycytidine and/or the histone deacetylase inhibitor trichostatin A greatly increased PACE4 expression in OC cells [12].
• The deduced PACE4C protein sequence (652 amino acids) lacks the cysteine-rich region located at the carboxy terminus of PACE4 [18].

Other interactions of PCSK6

• In vitro, 50% cleavage of pro-alpha subunits was obtained with one-third of the amount of PC5A and PACE4 than of furin [19].
• Northern blot analysis revealed that PACE4, furin and PC8 of the SPC family were expressed in HepG2 cells as well as in the liver [20].
• These inhibitors will be useful tools in helping us to understand the roles of PACE4, furin and PC6 [21].
• Development of selectivity of alpha1-antitrypsin variant by mutagenesis in its reactive site loop against proprotein convertase. A crucial role of the P4 arginine in PACE4 inhibition [21].
• Functional analysis of human PACE4-A and PACE4-C isoforms: identification of a new PACE4-CS isoform [14].

Analytical, diagnostic and therapeutic context of PCSK6

• Site-directed mutagenesis studies demonstrate that the proteolytic activation of SPC4 occurs mainly through a unimolecular autocatalytic process and propeptide cleavage is a prerequisite for its export from the ER [22].
• By in situ hybridization, Mash-2 (mammalian achaete-scute homologue 2) mRNA was found to be expressed in the spongiotrophoblast layer where PACE4 was not expressed [2].
• Understanding the functions of the widely expressed PCs (prohormone/proprotein convertases), including PC5/6, furin and PACE4 (paired basic amino acid cleaving enzyme 4), in animal models is difficult since individual knockouts of these PCs in mice exhibit early embryonic lethality [23].
• Immunoblotting detected furin and PACE4 proteins (both members of this family) to be present in the rat liver subcellular fraction containing insulin proreceptor processing activity [24].
• Confocal microscopy and biochemical analyses revealed that the CRD is essential for cell surface tethering of PC5A and PACE4 and that it colocalizes and coimmunoprecipitates with the full-length and C-terminal domain of TIMP-2 [25].

References