Alternative titles; symbols
HGNC Approved Gene Symbol: PCSK2
Cytogenetic location: 20p12.1 Genomic coordinates (GRCh38): 20:17,226,107-17,484,578 (from NCBI)
The subtilisin-like proprotein convertases are expressed extensively in mammalian neural and endocrine cells and play a major role in the proteolytic processing of both neuropeptide and peptide hormone precursors. PC2 is expressed at high levels in the islets of Langerhans, where it participates in the processing of proinsulin to insulin. Also see PC1 (162150).
Ohagi et al. (1992) observed expression of the chloramphenicol acetyltransferase reporter fusions containing the putative promoter region in insulinoma cells but not in hepatoma cells, consistent with the known tissue-specific pattern of expression of the PC2 gene. Analysis of the level of CAT activity with several deletion mutants identified the region from -1100 to -539 from the translation start site as essential for PC2 promoter activity.
During secretion, immature 75-kD proPC2 is cleaved to produce active 68-kD PC2 protein. Taylor et al. (1997) examined the secretion of the proPC2 peptide from COS cells. They found that cleavage was not necessary for PC2 secretion. However, proper folding of the protein was necessary for secretion, and sequences at the C-terminus appeared to stabilize the correct conformation of the protein.
Gabreels et al. (1998) showed 7B2 (173120) immunoreactivity in the supraoptic nucleus (SON) or the paraventricular nucleus (PVN) in only 3 of 5 Prader-Willi syndrome (PWS) patients. In contrast with 5 other PWS patients, the neurons in the hypothalamic SON and PVN of the two 7B2-immunonegative PWS patients also failed to show any reaction using 2 antibodies directed against processed vasopressin (VP). On the other hand, even these 2 cases reacted normally with 5 antibodies that recognize different parts of the VP precursor. The same patients had no PC2 immunoreactivity in the SON or PVN, whereas PC1 immunoreactivity was only slightly diminished. The authors concluded that in the VP neurons of 2 PWS patients, the amounts of 7B2 and PC2 present are greatly reduced, resulting in diminished VP precursor processing.
To evaluate the regulated expression of the human PC2 gene, Ohagi et al. (1992) analyzed its structure and its promoter. The gene spans more than 130 kb and consists of 12 exons. Comparison with the structure of the gene encoding human furin (136950), another member of this superfamily, showed a high degree of conservation of exon/intron junctions. They found that the 5-prime flanking region is very G+C rich and contains 6 potential Sp1 binding sites but no TATA or CAT box.
Seidah et al. (1991) mapped the NEC2 gene to human chromosome 20p11.2-p11.1 and to mouse chromosome 2. Copeland et al. (1992) refined the regional localization in the mouse. By in situ hybridization, Ohagi et al. (1992) mapped the PC2 gene to 20p11.2. By radiation hybrid mapping, Maglott et al. (1996) localized the SNAP (600322), PCSK2, and THBD (188040) genes to a region corresponding to 20p11.2.
Homozygous Pc2-null mice grow normally and are generally healthy but have altered carbohydrate metabolism characterized by mild hypoglycemia and flattened glucose-tolerance curves (Furuta et al., 1997). They also show impaired processing of insulin, glucagon, and somatostatin (Furuta et al., 1998). Furuta et al. (2001) examined the biosynthesis and processing of proglucagon in isolated islets from these mice via pulse-chase labeling and found that proglucagon undergoes essentially no processing in chase periods up to 8 hours. Ultrastructural and immunocytochemical studies indicated the presence of large amounts of proglucagon in atypical-appearing secretory granules in the hyperplastic and hypertrophic A-cells, along with morphological evidence of high rates of proglucagon secretion in Pc2-null mice.
Copeland, N. G., Gilbert, D. J., Chretien, M., Seidah, N. G., Jenkins, N. A. Regional localization of three convertases, PC1 (Nec-1), PC2 (Nec-2), and furin (Fur), on mouse chromosomes. Genomics 13: 1356-1358, 1992. [PubMed: 1354647] [Full Text: https://doi.org/10.1016/0888-7543(92)90069-5]
Furuta, M., Carroll, R., Martin, S., Swift, H. H., Ravazzola, M., Orci, L., Steiner, D. F. Incomplete processing of proinsulin to insulin accompanied by elevation of Des-31,32 proinsulin intermediates in islets of mice lacking active PC2. J. Biol. Chem. 273: 3431-3437, 1998. [PubMed: 9452465] [Full Text: https://doi.org/10.1074/jbc.273.6.3431]
Furuta, M., Yano, H., Zhou, A., Rouille, Y., Holst, J. J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H., Steiner, D. F. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc. Nat. Acad. Sci. 94: 6646-6651, 1997. [PubMed: 9192619] [Full Text: https://doi.org/10.1073/pnas.94.13.6646]
Furuta, M., Zhou, A., Webb, G., Carroll, R., Ravazzola, M., Orci, L., Steiner, D. F. Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. J. Biol. Chem. 276: 27197-27202, 2001. [PubMed: 11356850] [Full Text: https://doi.org/10.1074/jbc.M103362200]
Gabreels, B. A. T. F., Swaab, D. F., de Kleijn, D. P. V., Seidah, N. G., Van de Loo, J.-W., Van de Ven, W. J. M., Martens, G. J. M., van Leeuwen, F. W. Attenuation of the polypeptide 7B2, prohormone convertase PC2, and vasopressin in the hypothalamus of some Prader-Willi patients: indications for a processing defect. J. Clin. Endocr. Metab. 83: 591-599, 1998. [PubMed: 9467579] [Full Text: https://doi.org/10.1210/jcem.83.2.4542]
Maglott, D. R., Feldblyum, T. V., Durkin, A. S., Nierman, W. C. Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p). Mammalian Genome 7: 400-401, 1996. [PubMed: 8661740] [Full Text: https://doi.org/10.1007/s003359900120]
Ohagi, S., LaMendola, J., LeBeau, M. M., Espinosa, R., III, Takeda, J., Smeekens, S. P., Chan, S. J., Steiner, D. F. Identification and analysis of the gene encoding human PC2, a prohormone convertase expressed in neuroendocrine tissues. Proc. Nat. Acad. Sci. 89: 4977-4981, 1992. [PubMed: 1594602] [Full Text: https://doi.org/10.1073/pnas.89.11.4977]
Seidah, N. G., Mattei, M. G., Gaspar, L., Benjannet, S., Mbikay, M., Chretien, M. Chromosomal assignments of the genes for neuroendocrine convertase PC1 (NEC1) to human 5q15-21, neuroendocrine convertase PC2 (NEC2) to human 20p11.1-11.2, and furin (mouse 7[D1-E2] region). Genomics 11: 103-107, 1991. [PubMed: 1765368] [Full Text: https://doi.org/10.1016/0888-7543(91)90106-o]
Taylor, N. A., Shennan, K. I. J., Cutler, D. F., Docherty, K. Mutations within the propeptide, the primary cleavage site or the catalytic site, or deletion of C-terminal sequences, prevents secretion of proPC2 from transfected COS-7 cells. Biochem. J. 321: 367-373, 1997. [PubMed: 9020868] [Full Text: https://doi.org/10.1042/bj3210367]