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Gene Review

Pcsk1  -  proprotein convertase subtilisin/kexin type 1

Rattus norvegicus

Synonyms: BDP, Bdp, NEC 1, Nec-1, Nec1, ...
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Disease relevance of Pcsk1

  • A 5.0-kilobase (kb) cDNA, termed BDP, coding for a 752-amino acid protein and a 2.5-kb cDNA coding for a 636-amino acid protein, which was found to be the rat equivalent of the human insulinoma PC2 protein, were isolated [1].
  • In the adenopituitary, POMC mRNA levels were decreased after dehydration but PC1 mRNA levels were unaffected [2].
  • 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 [3].
  • To investigate whether prohormone convertases are involved in ProNPY processing, a vaccinia virus derived expression system was used to coexpress recombinant ProNPY with each of the prohormone convertases PC1/3, PC2, furin, and PACE4 in Neuro2A and NIH 3T3 cell lines as regulated neuroendocrine and constitutive prototype cell lines, respectively [4].
  • In this study, we demonstrated that 6-n-propyl-2-thiouracil (PTU)-induced hypothyroidism stimulated, whereas triido-L-thyronine (T(3))-induced hyperthyroidism suppressed, PC1 mRNA levels in the rat anterior pituitary [5].

Psychiatry related information on Pcsk1

  • The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease [6].

High impact information on Pcsk1

  • A decrease in the islet content of PC2, PC3, and CP-H from hyperglycemic rats was observed [7].
  • The assay reconstitutes homotypic fusion between one population of ISGs containing a [35S]sulfate-labeled substrate, secretogranin II (SgII), and a second population containing the prohormone convertase PC2 [8].
  • In the present work we have stably transfected neuroendocrine cell lines with rat 7B2 constructs and found that overexpression of 27 kD 7B2 greatly facilitates the kinetics of maturation of proPC2, both in AtT-20/PC2 cells and in Rin5f cells [9].
  • To correlate effects on PC2 maturation with the actual generation of PC2 enzymatic activity, a similar transfection of 21 kD 7B2 was performed using CHO cells previously amplified for the expression of proPC2 [9].
  • The prohormone convertase PC2, which is thought to mediate the proteolytic conversion of many peptide hormones, has recently been shown to interact with the neuroendocrine-specific polypeptide 7B2 in Xenopus intermediate lobe (Braks, J. A. M., and G. J. M. Martens. Cell. 78:263. 1994) [9].

Chemical compound and disease context of Pcsk1


Biological context of Pcsk1

  • Further transfection analysis identified the sorting sequence as a compact C-terminal alpha-helix and embedded 564RRR566 PC cleavage site; mutation of the 564RRR566 PC site in VGF-(1-65): GFP:VGF-(545-617) blocked regulated secretion, whereas disruption of the alpha-helix had no effect [13].
  • During the development of rat pancreatic islets, the prohormone convertases, PC2 and PC3, appear during late gestation and are expressed long after birth [14].
  • Among the convertases studied, only PC1 messenger RNA displayed up-regulation, with temporal and topographic features comparable to those of nerve growth factor and brain-derived neurotrophic factor messenger RNA [15].
  • We conclude that PC2 is the key endoprotease responsible for proglucagon processing in cells with the alpha-cell phenotype [16].
  • We speculate that (a) PC2 undergoes unusual glycosylation, which may be related to its slow release from cells, and (b) the 64-kDa molecule detectable in spent Rin cell medium represents the enzymatically active form of PC2 [17].

Anatomical context of Pcsk1

  • We now report that when pro-TRH is transiently expressed in GH4C1 cells, a neuroendocrine cell line lacking PC1, under pulse-chase conditions release is constitutive and composed of more immature processing intermediates [18].
  • These results indicated that initial processing action of PC1 on pro-TRH in the trans-Golgi network, and not a cargo-receptor relationship, is important for the downstream sorting events that result in storage of pro-TRH-derived peptides in mature secretory granules [18].
  • Furthermore, pro-NT/NN was processed in these compartments according to a pattern that differed from that previously described in PC1- and PC2-transfected PC12 cells [19].
  • 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 [20].
  • PC2 was found in A and in some D cells more than in B cells and PC1 was evident only in B cells [21].

Associations of Pcsk1 with chemical compounds


Co-localisations of Pcsk1


Regulatory relationships of Pcsk1

  • A moderate to high percentage of CCK mRNA-positive neurons express PC1 mRNA [26].
  • METHODS AND RESULTS: Here, we show that after MI, the expression of pro-TRH is induced in the heart coordinately with the protease PC1, an important enzyme in TRH biosynthesis [27].
  • In general, PC2 was more widely expressed than PC1 in the CNS, although many regional variations were detected [28].

Other interactions of Pcsk1


Analytical, diagnostic and therapeutic context of Pcsk1


  1. Isolation of two complementary deoxyribonucleic acid clones from a rat insulinoma cell line based on similarities to Kex2 and furin sequences and the specific localization of each transcript to endocrine and neuroendocrine tissues in rats. Hakes, D.J., Birch, N.P., Mezey, A., Dixon, J.E. Endocrinology (1991) [Pubmed]
  2. Perinatal food deprivation induces marked alterations of the hypothalamo-pituitary-adrenal axis in 8-month-old male rats both under basal conditions and after a dehydration period. Sebaai, N., Lesage, J., Breton, C., Vieau, D., Deloof, S. Neuroendocrinology (2004) [Pubmed]
  3. Proinsulin processing in the rat insulinoma cell line INS after overexpression of the endoproteases PC2 or PC3 by recombinant adenovirus. Irminger, J.C., Meyer, K., Halban, P. Biochem. J. (1996) [Pubmed]
  4. Role of prohormone convertases in pro-neuropeptide Y processing: coexpression and in vitro kinetic investigations. Brakch, N., Rist, B., Beck-Sickinger, A.G., Goenaga, J., Wittek, R., Bürger, E., Brunner, H.R., Grouzmann, E. Biochemistry (1997) [Pubmed]
  5. Regulation of prohormone convertase 1 (PC1) by thyroid hormone. Li, Q.L., Jansen, E., Brent, G.A., Friedman, T.C. Am. J. Physiol. Endocrinol. Metab. (2001) [Pubmed]
  6. The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease. Winsky-Sommerer, R., Grouselle, D., Rougeot, C., Laurent, V., David, J.P., Delacourte, A., Dournaud, P., Seidah, N.G., Lindberg, I., Trottier, S., Epelbaum, J. Neuroscience (2003) [Pubmed]
  7. Increased secretory demand rather than a defect in the proinsulin conversion mechanism causes hyperproinsulinemia in a glucose-infusion rat model of non-insulin-dependent diabetes mellitus. Alarcón, C., Leahy, J.L., Schuppin, G.T., Rhodes, C.J. J. Clin. Invest. (1995) [Pubmed]
  8. Homotypic fusion of immature secretory granules during maturation in a cell-free assay. Urbé, S., Page, L.J., Tooze, S.A. J. Cell Biol. (1998) [Pubmed]
  9. 7B2 facilitates the maturation of proPC2 in neuroendocrine cells and is required for the expression of enzymatic activity. Zhu, X., Lindberg, I. J. Cell Biol. (1995) [Pubmed]
  10. Enzymic characterization in vitro of recombinant proprotein convertase PC4. Basak, A., Touré, B.B., Lazure, C., Mbikay, M., Chrétien, M., Seidah, N.G. Biochem. J. (1999) [Pubmed]
  11. Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase. Shen, R., Sumitomo, M., Dai, J., Harris, A., Kaminetzky, D., Gao, M., Burnstein, K.L., Nanus, D.M. Endocrinology (2000) [Pubmed]
  12. Identification of genes related to invasion and metastasis in pancreatic cancer by cDNA representational difference analysis. Ishikawa, S., Egami, H., Kurizaki, T., Akagi, J., Tamori, Y., Yoshida, N., Tan, X., Hayashi, N., Ogawa, M. J. Exp. Clin. Cancer Res. (2003) [Pubmed]
  13. A prohormone convertase cleavage site within a predicted alpha-helix mediates sorting of the neuronal and endocrine polypeptide VGF into the regulated secretory pathway. Garcia, A.L., Han, S.K., Janssen, W.G., Khaing, Z.Z., Ito, T., Glucksman, M.J., Benson, D.L., Salton, S.R. J. Biol. Chem. (2005) [Pubmed]
  14. Developmental expression of proprotein-processing endoprotease furin in rat pancreatic islets. Kayo, T., Konda, Y., Tanaka, S., Takata, K., Koizumi, A., Takeuchi, T. Endocrinology (1996) [Pubmed]
  15. Pilocarpine-induced seizures are accompanied by a transient elevation in the messenger RNA expression of the prohormone convertase PC1 in rat hippocampus: comparison with nerve growth factor and brain-derived neurotrophic factor expression. Marcinkiewicz, M., Nagao, T., Day, R., Seidah, N.G., Chrétien, M., Avoli, M. Neuroscience (1997) [Pubmed]
  16. Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC1-6 cells. Rouillé, Y., Westermark, G., Martin, S.K., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  17. Biosynthesis of the prohormone convertase PC2 in Chinese hamster ovary cells and in rat insulinoma cells. Shen, F.S., Seidah, N.G., Lindberg, I. J. Biol. Chem. (1993) [Pubmed]
  18. Prohormone-convertase 1 processing enhances post-Golgi sorting of prothyrotropin-releasing hormone-derived peptides. Mulcahy, L.R., Vaslet, C.A., Nillni, E.A. J. Biol. Chem. (2005) [Pubmed]
  19. PC5-A-mediated processing of pro-neurotensin in early compartments of the regulated secretory pathway of PC5-transfected PC12 cells. Barbero, P., Rovère, C., De Bie, I., Seidah, N., Beaudet, A., Kitabgi, P. J. Biol. Chem. (1998) [Pubmed]
  20. Proparathyroid hormone processing by the proprotein convertase-7: comparison with furin and assessment of modulation of parathyroid convertase messenger ribonucleic acid levels by calcium and 1,25-dihydroxyvitamin D3. Canaff, L., Bennett, H.P., Hou, Y., Seidah, N.G., Hendy, G.N. Endocrinology (1999) [Pubmed]
  21. Distribution of the Kexin family proteases in pancreatic islets: PACE4C is specifically expressed in B cells of pancreatic islets. Nagamune, H., Muramatsu, K., Akamatsu, T., Tamai, Y., Izumi, K., Tsuji, A., Matsuda, Y. Endocrinology (1995) [Pubmed]
  22. Prohormone convertase 1 is necessary for the formation of cholecystokinin 8 in Rin5F and STC-1 cells. Yoon, J., Beinfeld, M.C. J. Biol. Chem. (1997) [Pubmed]
  23. Expression of the proprotein convertases PC1 and PC2 mRNAs in thyrotropin releasing hormone neurons of the rat paraventricular nucleus of hypothalamus. Sánchez, E., Charli, J.L., Morales, C., Corkidi, G., Seidah, N.G., Joseph-Bravo, P., Uribe, R.M. Brain Res. (1997) [Pubmed]
  24. Prohormone convertase 1 (PC1) when expressed with pro cholecystokinin (pro CCK) in L cells performs three endoproteolytic cleavages which are observed in rat brain and in CCK-expressing endocrine cells in culture, including the production of glycine and arginine extended CCK8. Wang, W., Birch, N.P., Beinfeld, M.C. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  25. The proprotein convertase furin colocalizes with caveolin-1 in the Golgi apparatus and endosomes of hepatocytes. Mayer, G., Boileau, G., Bendayan, M. Cell Tissue Res. (2004) [Pubmed]
  26. Genetic inactivation of prohormone convertase (PC1) causes a reduction in cholecystokinin (CCK) levels in the hippocampus, amygdala, pons and medulla in mouse brain that correlates with the degree of colocalization of PC1 and CCK mRNA in these structures in rat brain. Cain, B.M., Connolly, K., Blum, A.C., Vishnuvardhan, D., Marchand, J.E., Zhu, X., Steiner, D.F., Beinfeld, M.C. J. Neurochem. (2004) [Pubmed]
  27. Thyrotropin-releasing hormone is induced in the left ventricle of rats with heart failure and can provide inotropic support to the failing heart. Jin, H., Fedorowicz, G., Yang, R., Ogasawara, A., Peale, F., Pham, T., Paoni, N.F. Circulation (2004) [Pubmed]
  28. Gene expression of prohormone and proprotein convertases in the rat CNS: a comparative in situ hybridization analysis. Schäfer, M.K., Day, R., Cullinan, W.E., Chrétien, M., Seidah, N.G., Watson, S.J. J. Neurosci. (1993) [Pubmed]
  29. Stepwise posttranslational processing of progrowth hormone-releasing hormone (proGHRH) polypeptide by furin and PC1. Posner, S.F., Vaslet, C.A., Jurofcik, M., Lee, A., Seidah, N.G., Nillni, E.A. Endocrine (2004) [Pubmed]
  30. Mutational analysis of predicted interactions between the catalytic and P domains of prohormone convertase 3 (PC3/PC1). Ueda, K., Lipkind, G.M., Zhou, A., Zhu, X., Kuznetsov, A., Philipson, L., Gardner, P., Zhang, C., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  31. Secretion of soluble leptin receptors by exocrine and endocrine cells of the gastric mucosa. Cammisotto, P.G., Gingras, D., Renaud, C., Levy, E., Bendayan, M. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  32. Identification of the thyrotropin-releasing hormone precursor, its processing products, and its coexpression with convertase 1 in primary cultures of hypothalamic neurons: anatomic distribution of PC1 and PC2. Nillni, E.A., Luo, L.G., Jackson, I.M., McMillan, P. Endocrinology (1996) [Pubmed]
  33. Processing of prodynorphin in BRL-3A cells, a rat liver-derived cell line: implications for the specificity of neuropeptide-processing enzymes. Petanceska, S., Zikherman, J., Fricker, L.D., Devi, L. Mol. Cell. Endocrinol. (1993) [Pubmed]
  34. Expression of antisense PC1 in stably transfected RIN5F cells significantly reduces CCK 8 biosynthesis. Yoon, J.Y., Beinfeld, M.C. Regul. Pept. (1995) [Pubmed]
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