Disease relevance of PCSK1

• 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 [1].
• Noticeably, the proportion of glucagon-producing cells immunoreactive for PC3 was high in the gut and low in pancreatic islets and glucagonomas, whereas the reverse occurred for PC2 [2].
• Among 58 pituitary adenomas obtained by trans-sphenoidal surgery, adrenocorticotropin (ACTH)-secreting adenomas showed a high incidence of the presence of PC1/3 and PC2, i.e., nine of nine cases were positive for ACTH [3].
• The high incidence of PC1/3 and PC2 in nonfunctioning adenomas might be related to the processing of chromogranin A [3].
• PC1 mRNA was undetected in squamous cell carcinomas and in all but two adenocarcinomas; it was present in four of six SCLCs [4].

Psychiatry related information on PCSK1

• PC1 and PC2 were positively associated with age, education, physical activity, and nonsmoking status [5].

High impact information on PCSK1

• When incubated in vitro with newly synthesized pituitary proteins, recombinant 7B2 specifically associates with prohormone convertase PC2 [6].
• Three group C monoclonal antibodies (PC-1, PC-3, and PC-4) were specific for platelet glycoprotein IIb/IIIa [7].
• Our results demonstrate that PC-dependent cleavage regulates melanosome biogenesis by controlling the fibrillogenic activity of a resident protein [8].
• Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis [8].
• We identify the protease accomplishing the first cleavage as furin, a proprotein convertase [9].

Chemical compound and disease context of PCSK1

• It is suggested here that DASM, by virtue of this protease inhibitory property, possibly acts by suppressing the proteolytic cleavage of envelope glycoprotein gp160 of HIV, which is known to be PC-mediated, particularly by furin and PC7 [10].
• 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 [11].
• Our results pointed out a relationship between PC1 (PCBs, PBDE, DDE, and DDT compounds) and interfollicular fibrosis in the harbour porpoise thyroids [12].
• The in vivo antitumor activity of BBL22 was examined in a human xenograft model of androgen-independent prostate cancer where BBL22 significantly reduced the growth of PC3 prostate tumors without eliciting overt toxicity [13].
• Selected missense mutations in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) cause autosomal dominant hypercholesterolemia, whereas nonsense mutations in the same gene are associated with low plasma levels of low-density lipoprotein cholesterol (LDL-C) [14].

Biological context of PCSK1

• Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death [15].
• Proprotein conversion is determined by a multiplicity of factors including convertase processing, substrate specificity, and intracellular environment. Cell type-specific processing of human prorenin by the convertase PC1 [1].
• Although both PCs were virtually universal concomitants of the neuroendocrine system, cells with a neural phenotype (e.g. pheochromocytes and Merkel cells) predominantly contained PC2, whereas classic endocrine cells contained mostly PC3 [2].
• Differential modulation of prohormone convertase mRNA by second messenger activators in two cholecystokinin-producing cell lines [16].
• Site-specific mutagenesis experiments demonstrate that two closely spaced cAMP response elements within the proximal promoter region direct cAMP-mediated hormonal regulation of transcription of the PC1 gene [17].

Anatomical context of PCSK1

• Using human prorenin as a model, we show that PC1 can process it to active renin in cells containing secretory granules, such as the somatomammotroph cell line GH4, but not in cells which lack granules, such as the Chinese hamster ovary or African green monkey kidney epithelial (BSC-40) cell lines [1].
• We isolated a cDNA clone encoding the human prohormone convertase PC5 from human adrenal gland mRNA [18].
• Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex [18].
• PC3 immunoreactive cells were abundant all along the gastrointestinal tract, whereas PC2 was highly expressed only in the pyloric antrum and proximal third of duodenum [2].
• Double immunostaining experiments revealed colocalization of PC3 with virtually all gastrointestinal peptides, whereas PC2 immunoreactivity was mostly expressed in gastrin, cholecystokinin, and somatostatin cells [2].

Associations of PCSK1 with chemical compounds

• Activation of both cAMP and PKC pathways increased PC1, but not PC2 or furin mRNA levels in SK-N-MCIXC cells [16].
• The Km values for human PC1 and human furin were 17 microM and 30 microM respectively, with Vmax. values of 6.4 microM/h and 18 microM/h. These values differ significantly from those obtained when using a 7-amino-4-methylcoumarin-containing pentapeptidyl substrate where, for similar Km values, the Vmax. values were much lower [19].
• Among PPARgamma2 P12P carriers also fasting insulin and glucose levels during OGTT were higher in PC-1 X121Q than in K121K individuals [20].
• We conclude that there are multiple novel TRE-like sequences in the hPC1 promoter and that these regions act in a unique manner to facilitate the negative effect of thyroid hormone on PC1 [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 [22].

Physical interactions of PCSK1

• Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network [23].
• 7B2 is a neuroendocrine chaperone that transiently interacts with prohormone convertase PC2 in the secretory pathway [6].

Enzymatic interactions of PCSK1

• Purified recombinant furin and PC1 cleaved the human pro-PTH internally quenched substrate at the appropriate site in an identical manner to that observed with the nonfluorescent peptide [24].
• Previous studies have demonstrated that the mouse proprotein convertase PC1 (mPC1) accurately cleaves human prorenin to generate active renin and that this processing event appears to require co-packaging in secretory granules [25].
• The inability of PC2 and PC3 to cleave vWF was apparently not due to the absence of a transmembrane domain, since deletion of the transmembrane domain from PACE resulted in a secreted form which retained its propeptide processing activity within the secretory apparatus [26].
• PC3 cleaves proinsulin first to generate a proinsulin conversion intermediate that is the preferred substrate of PC2 [27].

Regulatory relationships of PCSK1

• The expression of proprotein convertase PACE4 is highly regulated by Hash-2 in placenta: possible role of placenta-specific basic helix-loop-helix transcription factor, human achaete-scute homologue-2 [28].
• None of the 7B2 mutant proteins inhibited PC1/PC3 activity [29].
• We hypothesized that thyroid hormone status in specific nuclei of the brain would alter pro-TRH processing by inducing changes in PC1/3 and PC2 expression [11].
• ACTH producing adenomas were observed to express PC3 mRNA [30].
• Moreover, these findings suggest that the malfunction of PC-1 enhances plasma membrane expression of CFTR, thus causing abnormal Cl(-)secretion into the cyst lumen [31].

Other interactions of PCSK1

• We also examined the susceptibility of PCSK9 to proteolytic cleavage by the other members of the PC family [32].
• Processing of pro-islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2 [33].
• CONCLUSION: The Mediterranean-like PC1-score as well as the vegetarian-like PC2 were higher among older, more educated people, and were associated with a healthier lifestyle than PC4, which reflected a Western-type diet [5].
• These results suggest that autoantibodies against PC1/3 and 7B2 are novel tumor-associated autoantibodies and can be helpful in the diagnosis of clinically nonfunctioning pituitary macroadenoma [34].
• 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 [35]?

Analytical, diagnostic and therapeutic context of PCSK1

• By immunocytochemistry and immunoblotting, we examined normal and neoplastic human tissues with polyclonal antibodies raised against selected peptide regions of proprotein convertase-2 and -3 (PC2 and PC3), two proteases that have been shown to selectively cleave neuroendocrine precursor molecules at pairs of basic residues [2].
• Transcripts for both PC1 and furin convertase were detectable in skin-derived mast cells and HMC-1 cells, as shown by RT-PCR [36].
• PC1 was strongly positively associated with an a priori Mediterranean-diet score [5].
• The expressions of PC1/3 mRNA and PC2 mRNA detected by in situ hybridization in the bronchial carcinoids and rectal carcinoids were correlated with immunoexpressions of both of the antigens [37].
• 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 [37].

References