Disease relevance of PCSK2

• Since non-insulin-dependent diabetes mellitus (NIDDM) is associated with increased secretion of proinsulin and proinsulin-like molecules, we conducted a case-control study to determine whether a genetic variation in PCSK2 might contribute to the development of NIDDM [1].
• Expression of chloramphenicol acetyltransferase reporter fusions containing the putative promoter region was observed to occur in beta TC-3 mouse insulinoma cells but not in HepG2 human hepatoma cells, consistent with the known tissue-specific pattern of expression of the hPC2 gene [2].
• Using the vaccinia virus expression system, biosynthetic labeling experiments demonstrated that PC1 and PC2 are themselves cleaved intracellularly at pairs of basic residues and that these two proenzymes are processed to different extents independent of whether the cell line contains dense core secretory granules [3].
• We postulate that the alterations of PC2 activity may mediate some of the pathophysiological consequences of hypo- or hyperthyroidism [4].
• PC2 mRNA was found in two adenocarcinomas, in one squamous cell carcinoma and in five of seven SCLCs [5].

Psychiatry related information on PCSK2

• PC1 and PC2 were positively associated with age, education, physical activity, and nonsmoking status [6].

High impact information on PCSK2

• Among the members of the prohormone convertase (PC) family, PC2 has a unique maturation pattern: it is retained in the ER for a comparatively long time and its propeptide is cleaved in the TGN/ secretory granules rather than in the ER [7].
• The serine protease prohormone convertase 2 (PC2), principally involved in the processing of polypeptide hormone precursors in neuroendocrine tissues, requires interaction with the neuroendocrine protein 7B2 to generate an enzymatically active form [8].
• Internal cleavage of the inhibitory 7B2 carboxyl-terminal peptide by PC2: a potential mechanism for its inactivation [9].
• The amino acid sequence of preproSPC2 contains 689 aa and is 71% identical to human SPC2 [10].
• SPC2 and SPC3 are two members of a family of subtilisin-related proteases which play essential roles in the processing of prohormones into their mature forms in the pancreatic B cell and many other neuroendocrine cells [10].

Chemical compound and disease context of PCSK2

• In the current study, we examined the in vivo regulation of brain PC2 mRNA by thyroid status and found that 6-n-propyl-2-thiouracil-induced hypothyroidism stimulated, whereas thyroxine-induced hyperthyroidism suppressed, PC2 mRNA levels in the rat hypothalamus and cerebral cortex [11].
• Expression of PC2 was considered to induce hyperpigmentation by producing alpha MSH [12].
• The vasopressin precursor is not processed in the hypothalamus of Wolfram syndrome patients with diabetes insipidus: evidence for the involvement of PC2 and 7B2 [13].
• Our results show that 6-n-propyl-2-thiouracil (PTU) treatment producing hypothyroidism induced a significant increase in the expression of PC1/3, PC2, and pro-TRH in the PVN and LH, but not VMN [14].

Biological context of PCSK2

• We have previously cloned and characterized the exon-intron organization of the human PC2 gene (gene symbol PCSK2), localized this gene to human chromosome 20 band p11.2 by fluorescence in situ hybridization, and identified a simple tandem-repeat DNA polymorphism (STRP) in intron 2 of the form (CA)n, suitable for genetic studies [1].
• The hPC2 gene was localized to chromosome 20, band p11 [2].
• In the present study, in vitro mutagenesis was used to identify the region within the 7B2 sequence responsible for the inhibition of PC2 [15].
• Plasmids encoding proPC2 and various 7B2s were transiently transfected into human embryonic kidney (HEK293) cells and PC2 enzymatic activity and CT forms in each overnight conditioned medium were measured [16].
• The screening of a larval cDNA library of the sheep blowfly Lucilia cuprina resulted in the isolation of two cDNAs encoding a PC2-like prohormone convertase [17].

Anatomical context of PCSK2

• Finally, the in vivo regulation of pituitary PC2 mRNA by thyroid status was demonstrated in rats [4].
• 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 [18].
• The mouse neuroblastoma cell line (Neuro 2 A) has been shown to contain the mRNA of a prohormone converting enzyme, PC2 [19].
• Bile duct carcinoids also demonstrated higher expressions of PC1/3 than those of PC2 [20].
• Our immunohistochemical studies disclosed the presence of PC1/3 and PC2 in non-neoplastic pituitary glands, especially in corticotrophs, gonadotrophs, and thyrotrophs [21].

Associations of PCSK2 with chemical compounds

• Analysis of the level of chloramphenicol acetyltransferase activity with several deletion mutants identified the region from -1100 to -539 from the translation start site as essential for hPC2 promoter activity [2].
• Interactions between the prohormone convertase 2 promoter and the thyroid hormone receptor [4].
• To address the mechanism of T3 regulation of the PC2 gene, we used human PC2 (hPC2) promoter constructs transiently transfected into GH3 cells and found that triiodothyronine negatively and 9-cis-retinoic acid positively regulated hPC2 promoter activity [11].
• Activation of both cAMP and PKC pathways increased PC1, but not PC2 or furin mRNA levels in SK-N-MCIXC cells [22].
• PC2 processes proIAPP preferably at the NH2-terminal processing site, and PC1/3 processes proIAPP exclusively at the COOH-terminal site [23].

Physical interactions of PCSK2

• In addition, we show that the transcription factor EGR-1 interacts with two distinct elements within the proximal human PC2 promoter region [24].
• In vitro binding and Far Western blot experiments demonstrated that PC2 and FPC are in the same complex only if KIF3B is present, presumably by forming a PC2-KIF3B-FPC complex [25].
• Site-directed mutagenesis of pro-PC2 further showed that a single residue replacement in the catalytic domain, Tyr-194 --> Asp, prevented pro-PC2 from binding 7B2 and blocked activation [26].
• These results suggest that the interaction of Pa with its target sequence(s) prevent PC2 binding and thereby contribute towards increased IGFBP-1 gene transcription [27].

Enzymatic interactions of PCSK2

• PC3 cleaves proinsulin first to generate a proinsulin conversion intermediate that is the preferred substrate of PC2 [28].

Regulatory relationships of PCSK2

• Transfection experiments also demonstrate that EGR-1 is able to enhance PC2 promoter activity [24].
• Previous studies have demonstrated that while the carboxyl-terminal portion of 7B2 (residues 155-186) regulates the enzymatic activity of PC2, the amino terminus of the molecule (residues 1-151) is required for maturation of proPC2 [29].
• PC2 mRNA was down regulated by NaB while PC1 mRNA was unchanged [30].
• Characterization of pro-opiomelanocortin processing in heterologous neuronal cells that express PC2 mRNA [31].

Other interactions of PCSK2

• In contrast, in both cell types, human prorenin is not activated by either PC2 or furin [3].
• Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p) [32].
• PC3 was active initially at the N-terminal-IAPP junction and later at the C-terminus, whereas initial PC2 activity was at the IAPP-C-terminal junction [33].
• We conclude that cleavage at the 7B2 furin consensus site is required to produce PC2 capable of efficient proteolytic inactivation of the CT peptide [16].
• Glucocorticoid treatment is associated with decreased expression of processed AVP but not of proAVP, neurophysin or oxytocin in the human hypothalamus: are PC1 and PC2 involved [34]?

Analytical, diagnostic and therapeutic context of PCSK2

• The granular immunoexpression pattern of PC1/3 and PC2 visualized by confocal laser scanning microscopy would suggest the site of post-translational processing in the secretory granules [20].
• A combination of site-directed mutagenesis and a cell-free translation/translocation system from Xenopus eggs was used to investigate the processing of the pro-PC2 precursor [35].
• To further investigate the function(s) of SPC2 and SPC3 in amphioxus, we have determined the regional expression of these genes by using a reverse transcriptase-linked polymerase chain reaction (RT-PCR) assay [10].
• Immunofluorescence experiments showed that PC2, FPC and KIF3B partially co-localized in primary cilia of over-confluent and perinuclear regions of sub-confluent cells [25].
• The USA-derived coactivators PC2 and PC4 fully reconstitute the USA coactivator activity, both by repressing the basal level of transcription and by potentiating activator function to yield large increases in the levels of transcription induction [36].

References