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Gene Review

Pcsk2  -  proprotein convertase subtilisin/kexin type 2

Mus musculus

Synonyms: 6330411F23Rik, AI839700, KEX2-like endoprotease 2, NEC 2, Nec-2, ...
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Disease relevance of Pcsk2

  • Mice lacking PC2 demonstrate multiple defects, including chronic mild hypoglycemia and dramatic hyperplasia of the pancreatic alpha-cells [1].
  • These insulin-synthesizing tumors expressed PC1 and PC2, whereas insulin-silent adenomas did not [2].
  • A recombinant vaccinia virus vector was used to coexpress the two candidate mouse prohormone convertases, PC1 and PC2, together with mouse proopiomelanocortin (POMC) in the constitutively secreting cell line BSC-40 and in the endocrine tissue-derived cell lines PC12 and AtT-20, which exhibit regulated secretion [3].
  • Convertase PC2 and the neuroendocrine polypeptide 7B2 are co-induced and processed during neuronal differentiation of P19 embryonal carcinoma cells [4].
  • In older PC2 mice (93-99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg [5].

High impact information on Pcsk2

  • 7B2 null mice have no demonstrable PC2 activity, are deficient in processing islet hormones, and display hypoglycemia, hyperproinsulinemia, and hypoglucagonemia [6].
  • In contrast to the PC2 null phenotype, these mice show markedly elevated circulating ACTH and corticosterone levels, with adrenocortical expansion [6].
  • Starvation of rats, leading to low serum leptin levels, decreased PC1 and PC2 gene and protein expression in the paraventricular nucleus (PVN) of the hypothalamus [7].
  • Administration of a stable analogue of gamma-MSH intra-abdominally by microosmotic pump to PC2(-/-) mice prevented the development of hypertension when ingesting the HSD [8].
  • Pcnt depletion by RNA interference disrupts basal body localization of IFT proteins and the cation channel polycystin-2 (PC2), and inhibits primary cilia assembly in human epithelial cells [9].

Chemical compound and disease context of Pcsk2


Biological context of Pcsk2


Anatomical context of Pcsk2

  • Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2 [15].
  • In contrast, GH4C1 and COS 7 cells, which express very little or no PC2 or PC3, failed to process proglucagon, aside from a low level of interdomain cleavage which occurred only in the GH4C1 cells [16].
  • Electron microscopy of neurointermediate lobe melanotrophs reveals the presence of a significantly greater number of secretory granules in both 7B2 and PC2 nulls compared with wild-type controls [17].
  • In addition, increased beta-endorphin1-31 was observed in pituitary and hypothalamus of PC2-deficient mice, suggesting beta-endorphin1-31 as a substrate for PC2 in these tissues [18].
  • Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and alpha-melanotropin [19].

Associations of Pcsk2 with chemical compounds

  • We have generated a strain of mice lacking active SPC2 by introducing the neomycin resistance gene (Neor) into the third exon of the mSPC2 gene [15].
  • Intraperitoneal delivery of 0.5 microg glucagon/h in PC2(-/-) mice resulted in the normalization of blood glucose concentrations [1].
  • We conclude that PC1/3 is important for processing of proIAPP at the COOH-terminus, but in its absence, PC2 can initiate complete processing of proIAPP to IAPP by cleaving the precursor at either its NH(2)- or COOH-terminal cleavage sites [20].
  • Biological processing of the cocaine and amphetamine-regulated transcript precursors by prohormone convertases, PC2 and PC1/3 [12].
  • PC2-null mice displayed a nine-fold increase of cerebral proCCK concentrations, and a two-fold increase in the concentrations of the processing-intermediate, glycine-extended CCK, whereas the concentrations of transmitter-active (i.e. alpha-amidated and O-sulfated) CCK peptides were reduced (61%) [21].

Physical interactions of Pcsk2

  • The expression of convertase PC2 and its specific binding peptide 7B2 are co-induced during neuronal differentiation of P19 cells [22].

Enzymatic interactions of Pcsk2

  • Both enzymes were able to cleave various KR- and KK-containing sites, but PC2 was also able to cleave efficiently at an RR-V site and a KK-M site not cleaved by PC1, suggesting the exclusion of large aliphatic residues at the P1' position in PC1 cleavage [23].

Co-localisations of Pcsk2


Regulatory relationships of Pcsk2

  • However, the IN(+) cells of d 15 PC2 mutant mice coexpressed glucagon, as did the first appearing beta-cells of controls [24].
  • Altered processing of pro-orphanin FQ/nociceptin and pro-opiomelanocortin-derived peptides in the brains of mice expressing defective prohormone convertase 2 [25].
  • The conditioned medium from furin-expressing MIN6 cells also exerted a decrease of PC2 and PC3 expression in unaltered MIN6 cells [26].
  • The neuroendocrine protein 7B2 and its 31-residue carboxyl-terminal (CT) peptide potently and specifically inhibit prohormone convertase 2 (PC2) [27].
  • Our results suggest that 7B2 possesses chaperone activity that blocks partially unfolded pro-PC2 forms from losing catalytic competence and then aggregating [28].

Other interactions of Pcsk2

  • In contrast, in PC2(-/-) mice, MAP on the LSD was not greater than in wild-type mice, but plasma gamma-MSH was reduced to one-seventh the wild-type value [8].
  • Mice lacking PC2 can process proIAPP at its COOH- but not its NH(2)-terminal cleavage site, suggesting that PC1/3 is capable of initiating proIAPP cleavage at its COOH-terminus [20].
  • The loss of prohormone convertase 2 alters CCK processing in specific brain regions [11].
  • Coexpression of proIAPP and PC2 resulted in production of mature IAPP, whereas in cells that coexpressed proIAPP and PC1/3 only a 6-kDa intermediate was produced [20].
  • However, PC2 null melanotrophs contain twice as many granules as 7B2 null melanotrophs [17].

Analytical, diagnostic and therapeutic context of Pcsk2


  1. Glucagon replacement via micro-osmotic pump corrects hypoglycemia and alpha-cell hyperplasia in prohormone convertase 2 knockout mice. Webb, G.C., Akbar, M.S., Zhao, C., Swift, H.H., Steiner, D.F. Diabetes (2002) [Pubmed]
  2. Developmental expression of the prohormone convertases PC1 and PC2 in mouse pancreatic islets. Marcinkiewicz, M., Ramla, D., Seidah, N.G., Chrétien, M. Endocrinology (1994) [Pubmed]
  3. PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Benjannet, S., Rondeau, N., Day, R., Chrétien, M., Seidah, N.G. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  4. Convertase PC2 and the neuroendocrine polypeptide 7B2 are co-induced and processed during neuronal differentiation of P19 embryonal carcinoma cells. Jeannotte, R., Paquin, J., Petit-Turcotte, C., Day, R. DNA Cell Biol. (1997) [Pubmed]
  5. Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism. Kawata, T., Imanishi, Y., Kobayashi, K., Kenko, T., Wada, M., Ishimura, E., Miki, T., Nagano, N., Inaba, M., Arnold, A., Nishizawa, Y. Eur. J. Endocrinol. (2005) [Pubmed]
  6. The neuroendocrine protein 7B2 is required for peptide hormone processing in vivo and provides a novel mechanism for pituitary Cushing's disease. Westphal, C.H., Muller, L., Zhou, A., Zhu, X., Bonner-Weir, S., Schambelan, M., Steiner, D.F., Lindberg, I., Leder, P. Cell (1999) [Pubmed]
  7. Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. Sanchez, V.C., Goldstein, J., Stuart, R.C., Hovanesian, V., Huo, L., Munzberg, H., Friedman, T.C., Bjorbaek, C., Nillni, E.A. J. Clin. Invest. (2004) [Pubmed]
  8. Genetic disruption of gamma-melanocyte-stimulating hormone signaling leads to salt-sensitive hypertension in the mouse. Ni, X.P., Pearce, D., Butler, A.A., Cone, R.D., Humphreys, M.H. J. Clin. Invest. (2003) [Pubmed]
  9. Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly. Jurczyk, A., Gromley, A., Redick, S., San Agustin, J., Witman, G., Pazour, G.J., Peters, D.J., Doxsey, S. J. Cell Biol. (2004) [Pubmed]
  10. Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. Furuta, M., Zhou, A., Webb, G., Carroll, R., Ravazzola, M., Orci, L., Steiner, D.F. J. Biol. Chem. (2001) [Pubmed]
  11. Cholecystokinin levels in prohormone convertase 2 knock-out mouse brain regions reveal a complex phenotype of region-specific alterations. Beinfeld, M.C., Blum, A., Vishnuvardhan, D., Fanous, S., Marchand, J.E. J. Biol. Chem. (2005) [Pubmed]
  12. Biological processing of the cocaine and amphetamine-regulated transcript precursors by prohormone convertases, PC2 and PC1/3. Dey, A., Xhu, X., Carroll, R., Turck, C.W., Stein, J., Steiner, D.F. J. Biol. Chem. (2003) [Pubmed]
  13. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Smeekens, S.P., Avruch, A.S., LaMendola, J., Chan, S.J., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  14. Characterization of a repressor element in the promoter region of proprotein convertase 2 (PC2) gene. Mbikay, M., Raffin-Sanson, M.L., Sirois, F., Kalenga, L., Chrétien, M., Seidah, N.G. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  15. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Furuta, M., Yano, H., Zhou, A., Rouillé, Y., Holst, J.J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  16. Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. Rouillé, Y., Martin, S., Steiner, D.F. J. Biol. Chem. (1995) [Pubmed]
  17. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Laurent, V., Jaubert-Miazza, L., Desjardins, R., Day, R., Lindberg, I. Endocrinology (2004) [Pubmed]
  18. Obliteration of alpha-melanocyte-stimulating hormone derived from POMC in pituitary and brains of PC2-deficient mice. Miller, R., Aaron, W., Toneff, T., Vishnuvardhan, D., Beinfeld, M.C., Hook, V.Y. J. Neurochem. (2003) [Pubmed]
  19. Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and alpha-melanotropin. Marcinkiewicz, M., Day, R., Seidah, N.G., Chrétien, M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  20. Role of beta-cell prohormone convertase (PC)1/3 in processing of pro-islet amyloid polypeptide. Marzban, L., Trigo-Gonzalez, G., Zhu, X., Rhodes, C.J., Halban, P.A., Steiner, D.F., Verchere, C.B. Diabetes (2004) [Pubmed]
  21. Increased synthesis but decreased processing of neuronal proCCK in prohormone convertase 2 and 7B2 knockout animals. Rehfeld, J.F., Lindberg, I., Friis-Hansen, L. J. Neurochem. (2002) [Pubmed]
  22. Coordinate regulation of neuroendocrine convertase PC2 and peptide 7B2 in P19 neurons. Petit-Turcotte, C., Paquin, J. Peptides (2000) [Pubmed]
  23. Cleavage of recombinant proenkephalin and blockade mutants by prohormone convertases 1 and 2: an in vitro specificity study. Peinado, J.R., Li, H., Johanning, K., Lindberg, I. J. Neurochem. (2003) [Pubmed]
  24. Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased alpha-cell proliferation, and islet neogenesis. Vincent, M., Guz, Y., Rozenberg, M., Webb, G., Furuta, M., Steiner, D., Teitelman, G. Endocrinology (2003) [Pubmed]
  25. Altered processing of pro-orphanin FQ/nociceptin and pro-opiomelanocortin-derived peptides in the brains of mice expressing defective prohormone convertase 2. Allen, R.G., Peng, B., Pellegrino, M.J., Miller, E.D., Grandy, D.K., Lundblad, J.R., Washburn, C.L., Pintar, J.E. J. Neurosci. (2001) [Pubmed]
  26. Proprotein-processing endoprotease furin decreases regulated secretory pathway-specific proteins in the pancreatic beta cell line MIN6. Kayo, T., Sawada, Y., Suzuki, Y., Suda, M., Tanaka, S., Konda, Y., Miyazaki, J., Takeuchi, T. J. Biol. Chem. (1996) [Pubmed]
  27. Structure-function analysis of the 7B2 CT peptide. Apletalina, E.V., Juliano, M.A., Juliano, L., Lindberg, I. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  28. 7B2 prevents unfolding and aggregation of prohormone convertase 2. Lee, S.N., Lindberg, I. Endocrinology (2008) [Pubmed]
  29. Processing of pro-opiomelanocortin in GH3 cells: inhibition by prohormone convertase 2 (PC2) antisense mRNA. Friedman, T.C., Cool, D.R., Jayasvasti, V., Louie, D., Loh, Y.P. Mol. Cell. Endocrinol. (1996) [Pubmed]
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