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Gene Review

PCSK1  -  proprotein convertase subtilisin/kexin type 1

Homo sapiens

Synonyms: BMIQ12, NEC 1, NEC1, Neuroendocrine convertase 1, PC1, ...
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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


High impact information on PCSK1


Chemical compound and disease context of PCSK1


Biological context of PCSK1


Anatomical context of PCSK1


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


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


  1. 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. Benjannet, S., Reudelhuber, T., Mercure, C., Rondeau, N., Chrétien, M., Seidah, N.G. J. Biol. Chem. (1992) [Pubmed]
  2. Proprotein convertases (PC1/PC3 and PC2) in normal and neoplastic human tissues: their use as markers of neuroendocrine differentiation. Scopsi, L., Gullo, M., Rilke, F., Martin, S., Steiner, D.F. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  3. Localization of prohormone convertases 1/3 and 2 in the human pituitary gland and pituitary adenomas: analysis by immunohistochemistry, immunoelectron microscopy, and laser scanning microscopy. Takumi, I., Steiner, D.F., Sanno, N., Teramoto, A., Osamura, R.Y. Mod. Pathol. (1998) [Pubmed]
  4. Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. Mbikay, M., Sirois, F., Yao, J., Seidah, N.G., Chrétien, M. Br. J. Cancer (1997) [Pubmed]
  5. Tracing the Mediterranean diet through principal components and cluster analyses in the Greek population. Costacou, T., Bamia, C., Ferrari, P., Riboli, E., Trichopoulos, D., Trichopoulou, A. European journal of clinical nutrition. (2003) [Pubmed]
  6. 7B2 is a neuroendocrine chaperone that transiently interacts with prohormone convertase PC2 in the secretory pathway. Braks, J.A., Martens, G.J. Cell (1994) [Pubmed]
  7. Human megakaryocytes. V. Changes in the phenotypic profile of differentiating megakaryocytes. Levene, R.B., Lamaziere, J.M., Broxmeyer, H.E., Lu, L., Rabellino, E.M. J. Exp. Med. (1985) [Pubmed]
  8. Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis. Berson, J.F., Theos, A.C., Harper, D.C., Tenza, D., Raposo, G., Marks, M.S. J. Cell Biol. (2003) [Pubmed]
  9. Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca(2+) stabilization. Chen, C.D., Huff, M.E., Matteson, J., Page, L., Phillips, R., Kelly, J.W., Balch, W.E. EMBO J. (2001) [Pubmed]
  10. Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters. Basak, A., Cooper, S., Roberge, A.G., Banik, U.K., Chrétien, M., Seidah, N.G. Biochem. J. (1999) [Pubmed]
  11. Cellular colocalization and coregulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism. Espinosa, V.P., Ferrini, M., Shen, X., Lutfy, K., Nillni, E.A., Friedman, T.C. Am. J. Physiol. Endocrinol. Metab. (2007) [Pubmed]
  12. Interfollicular fibrosis in the thyroid of the harbour porpoise: an endocrine disruption? Das, K., Vossen, A., Tolley, K., V??kingsson, G., Thron, K., M??ller, G., Baumg??rtner, W., Siebert, U. Arch. Environ. Contam. Toxicol. (2006) [Pubmed]
  13. Tumor selective G2/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine. Xia, W., Spector, S., Hardy, L., Zhao, S., Saluk, A., Alemane, L., Spector, N.L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  14. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Kotowski, I.K., Pertsemlidis, A., Luke, A., Cooper, R.S., Vega, G.L., Cohen, J.C., Hobbs, H.H. Am. J. Hum. Genet. (2006) [Pubmed]
  15. Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death. Marzban, L., Rhodes, C.J., Steiner, D.F., Haataja, L., Halban, P.A., Verchere, C.B. Diabetes (2006) [Pubmed]
  16. Differential modulation of prohormone convertase mRNA by second messenger activators in two cholecystokinin-producing cell lines. Mania-Farnell, B.L., Botros, I., Day, R., Davis, T.P. Peptides (1996) [Pubmed]
  17. Neuroendocrine-specific expression of the human prohormone convertase 1 gene. Hormonal regulation of transcription through distinct cAMP response elements. Jansen, E., Ayoubi, T.A., Meulemans, S.M., Van de Ven, W.J. J. Biol. Chem. (1995) [Pubmed]
  18. Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex. Mercure, C., Jutras, I., Day, R., Seidah, N.G., Reudelhuber, T.L. Hypertension (1996) [Pubmed]
  19. An internally quenched fluorogenic substrate of prohormone convertase 1 and furin leads to a potent prohormone convertase inhibitor. Jean, F., Basak, A., DiMaio, J., Seidah, N.G., Lazure, C. Biochem. J. (1995) [Pubmed]
  20. Evidence for genetic epistasis in human insulin resistance: the combined effect of PC-1 (K121Q) and PPARgamma2 (P12A) polymorphisms. Baratta, R., Di Paola, R., Spampinato, D., Fini, G., Marucci, A., Coco, A., Vigneri, R., Frittitta, L., Trischitta, V. J. Mol. Med. (2003) [Pubmed]
  21. Thyroid hormone regulation of prohormone convertase 1 (PC1): regional expression in rat brain and in vitro characterization of negative thyroid hormone response elements. Shen, X., Li, Q.L., Brent, G.A., Friedman, T.C. J. Mol. Endocrinol. (2004) [Pubmed]
  22. 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. Tsuji, A., Ikoma, T., Hashimoto, E., Matsuda, Y. Protein Eng. (2002) [Pubmed]
  23. Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network. Wang, P., Tortorella, M., England, K., Malfait, A.M., Thomas, G., Arner, E.C., Pei, D. J. Biol. Chem. (2004) [Pubmed]
  24. In vitro cleavage of internally quenched fluorogenic human proparathyroid hormone and proparathyroid-related peptide substrates by furin. Generation of a potent inhibitor. Lazure, C., Gauthier, D., Jean, F., Boudreault, A., Seidah, N.G., Bennett, H.P., Hendy, G.N. J. Biol. Chem. (1998) [Pubmed]
  25. Proteolytic processing of human prorenin in renal and non-renal tissues. Reudelhuber, T.L., Ramla, D., Chiu, L., Mercure, C., Seidah, N.G. Kidney Int. (1994) [Pubmed]
  26. Preferred sequence requirements for cleavage of pro-von Willebrand factor by propeptide-processing enzymes. Rehemtulla, A., Kaufman, R.J. Blood (1992) [Pubmed]
  27. What beta-cell defect could lead to hyperproinsulinemia in NIDDM? Some clues from recent advances made in understanding the proinsulin-processing mechanism. Rhodes, C.J., Alarcón, C. Diabetes (1994) [Pubmed]
  28. 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. Koide, S., Yoshida, I., Tsuji, A., Matsuda, Y. J. Biochem. (2003) [Pubmed]
  29. Identification of the region within the neuroendocrine polypeptide 7B2 responsible for the inhibition of prohormone convertase PC2. van Horssen, A.M., van den Hurk, W.H., Bailyes, E.M., Hutton, J.C., Martens, G.J., Lindberg, I. J. Biol. Chem. (1995) [Pubmed]
  30. Expression patterns of messenger ribonucleic acids encoding prohormone convertases (PC2 and PC3) in human pituitary adenomas. Hashimoto, K., Koga, M., Kouhara, H., Arita, N., Hayakawa, T., Kishimoto, T., Sato, B. Clin. Endocrinol. (Oxf) (1994) [Pubmed]
  31. A regulatory role of polycystin-1 on cystic fibrosis transmembrane conductance regulator plasma membrane expression. Ikeda, M., Fong, P., Cheng, J., Boletta, A., Qian, F., Zhang, X.M., Cai, H., Germino, G.G., Guggino, W.B. Cell. Physiol. Biochem. (2006) [Pubmed]
  32. The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and/or PC5/6A: FUNCTIONAL CONSEQUENCES OF NATURAL MUTATIONS AND POST-TRANSLATIONAL MODIFICATIONS. Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N.G. J. Biol. Chem. (2006) [Pubmed]
  33. Processing of pro-islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2. Badman, M.K., Shennan, K.I., Jermany, J.L., Docherty, K., Clark, A. FEBS Lett. (1996) [Pubmed]
  34. Frequent appearance of autoantibodies against prohormone convertase 1/3 and neuroendocrine protein 7B2 in patients with nonfunctioning pituitary macroadenoma. Tatsumi, K.I., Tanaka, S., Takano, T., Tahara, S., Murakami, Y., Takao, T., Hashimoto, K., Kato, Y., Teramoto, A., Amino, N. Endocrine (2003) [Pubmed]
  35. 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? Erkut, Z.A., Gabreëls, B.A., Eikelenboom, J., van Leeuwen, F.W., Swaab, D.F. Neuro Endocrinol. Lett. (2002) [Pubmed]
  36. Human mast cells in the neurohormonal network: expression of POMC, detection of precursor proteases, and evidence for IgE-dependent secretion of alpha-MSH. Artuc, M., Böhm, M., Grützkau, A., Smorodchenko, A., Zuberbier, T., Luger, T., Henz, B.M. J. Invest. Dermatol. (2006) [Pubmed]
  37. Immunohistochemical expressions of prohormone convertase (PC)1/3 and PC2 in carcinoids of various organs. Kajiwara, H., Itoh, Y., Itoh, J., Yasuda, M., Osamura, R.Y. Tokai J. Exp. Clin. Med. (1999) [Pubmed]
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