Disease relevance of Pcsk2

• To assess which of the subtilisin-like prohormone convertases can process proPTH to PTH we coinfected cells with a vaccinia virus construct expressing human preproPTH and vaccinia virus constructs expressing furin, PC1 or PC2 [1].
• Infection of INS cells with the corresponding recombinant adenovirus led to 5-10-fold and 20-40-fold increases in PC2 and PC3 expression respectively [2].
• We have now used recombinant adenovirus to overexpress PC2 or PC3 in the rat insulinoma cell line INS [2].
• Both PC1 and PC2 reduced the arrhythmia score in the controls (0.15 +/- 0.10 and 0.71 +/- 0.24, respectively), as well as in the hypoxic groups (0.40 +/- 0.15 and 0.27 +/- 0.15, respectively) [3].
• In the PC group the restraint haltering of the animals promoted presumably a stress situation with bile reflux in the non-operated whereas in the operated animals (PC2) reflux did not occur [4].

High impact information on Pcsk2

• Immunocytochemistry revealed that, although pancreatic islet cells in the STZ-treated rats were sparse and atrophic PC1, PC2, glucagon, and GLP-1 immunoreactivity increased dramatically in the remaining islet cells [5].
• Pancreatic PC1 and PC2 mRNA increased >2-fold and >4-fold, respectively, in rats receiving intraperitoneal STZ (50 mg/kg) daily for 5 days [5].
• A decrease in the islet content of PC2, PC3, and CP-H from hyperglycemic rats was observed [6].
• Enhanced PC2 expression was detected after irradiation of neuronal cultures but not in cultures of astrocytes, suggesting that the cell type in the CNS responsible for the PC2 induction after in vivo irradiation is the neuron [7].
• Previous studies demonstrated the distinct distribution of PC1, PC2, and furin mRNAs in the pituitary and brain, suggesting a unique function for each enzyme [8].

Biological context of Pcsk2

• 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].
• Modulation of prohormone convertase 2 in spinal cord during gestation and hormone-simulated pregnancy [10].
• One major product of 700 base pairs was obtained which was greater than 99% identical to the corresponding rat PC2 sequence [11].
• Deglycosylation studies using endoglycosidase H and N-glycanase showed that the 65-kDa protein was comprised of approximately 9% carbohydrate, consistent with the presence of three consensus sequences for N-linked glycosylation in rat PC2 [11].
• We conclude that (i) PC2 is the major pro-NT/NN convertase in rMTC 6-23 cells; (ii) its expression is coregulated with that of pro-NT/NN in this cell line; and (iii) PC2 and PC1 differentially process pro-NT/NN with brain and intestinal phenotype, respectively [12].

Anatomical context of Pcsk2

• This is in contrast to the processing of proinsulin to insulin in the pancreatic beta-cell, which is up-regulated by glucose stimulation of PC1 and PC2 synthesis [13].
• The biosynthesis of the subtilisin-related proprotein convertase PC3, but no that of the PC2 convertase, is regulated by glucose in parallel to proinsulin biosynthesis in rat pancreatic islets [14].
• In addition, PC12 cells were reported to be devoid of the prohormone convertases PC1 and PC2 [12].
• Localization of PC2 immunoreactivity to other tissues of the diffuse neuroendocrine system suggests that the type 2 endopeptidase also functions in the processing of precursor forms of other prohormones and polypeptide neurotransmitters [11].
• Moreover, the differential distribution of PC1 and PC2 mRNAs with pro-TRH mRNA may be responsible for the differential processing of this prohormone in the central nervous system [15].

Associations of Pcsk2 with chemical compounds

• PC2 expression was stimulated by dexamethasone in a time- and concentration-dependent manner [12].
• Our data showed that high levels of thyroid hormone down-regulated PC1/3 and PC2 and TRH synthesis, which led to an accumulation of intermediate forms of proTRH processing [16].
• Similarly, PC2, which was undetectable in control spleens, was induced in germinal centers following lipopolysaccharide treatment [17].
• In membranes of bovine chromaffin granules glycoprotein H was identified as the major PC2 immunoreactive spot [18].
• The expression of furin, PC2 and PC5 messenger RNA changed little, while PACE4 was not expressed at all, both before and after pilocarpine administration [19].

Regulatory relationships of Pcsk2

• In general, PC2 was more widely expressed than PC1 in the CNS, although many regional variations were detected [20].

Other interactions of Pcsk2

• Colocalization studies demonstrated that furin is expressed in the parathyroid, whereas proprotein convertase (PC)1 and PC2 are not [13].
• Both techniques gave similar results: PC2 mRNA was present in 60-70% of TRH neurons, and PC1 mRNA in 37-46% [21].
• The post-translational processing of chromogranin A in the pancreatic islet: involvement of the eukaryote subtilisin PC2 [22].
• Cellular colocalization studies using double in situ hybridization histochemistry showed the presence of PC2 mRNA in the pro-TRH neurons of the olfactory glomerular layer and basal lateral hypothalamus, and PC1 mRNA in the pro-TRH neurons in the paraventricular nucleus [15].
• PC1 immunoreactivity was concentrated in the Golgi apparatus, whereas PC2 immunoreactivity was prominent in the rough endoplasmic reticulum (RER) [23].

Analytical, diagnostic and therapeutic context of Pcsk2

• Using in situ hybridization, we observed PC1 and PC5 mRNAs in PVN and SON magnocellular neurons, while PC2 mRNA was observed in both magnocellular and parvocellular PVN neurons as well as magnocellular SON neurons [24].
• N-terminal sequence analysis of the immunoreactive protein gave two sequences which corresponded to residues 109-112 and 112-119 of rat PC2 [11].
• Western blot analyses of isolated islets revealed little difference in PC1 and CPE expression but PC2 immunoreactivity was markedly lower in the GK islets [25].
• Although undetectable by Northern blot analysis, both PC1 and PC2 mRNA were detected by in situ hybridization and immunohistochemistry in discrete regions of the intracardiac para-aortic ganglia [26].
• Preconditioning was induced by either two (PC1) or five (PC2) occlusions of the same artery for 5 min, each followed by 5-min reperfusion [3].

References