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PCSK2  -  proprotein convertase subtilisin/kexin type 2

Homo sapiens

Synonyms: KEX2-like endoprotease 2, NEC 2, NEC-2, NEC2, Neuroendocrine convertase 2, ...
 
 
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Disease relevance of PCSK2

 

Psychiatry related information on PCSK2

 

High impact information on PCSK2

  • Among the members of the prohormone convertase (PC) family, PC2 has a unique maturation pattern: it is retained in the ER for a comparatively long time and its propeptide is cleaved in the TGN/ secretory granules rather than in the ER [7].
  • The serine protease prohormone convertase 2 (PC2), principally involved in the processing of polypeptide hormone precursors in neuroendocrine tissues, requires interaction with the neuroendocrine protein 7B2 to generate an enzymatically active form [8].
  • Internal cleavage of the inhibitory 7B2 carboxyl-terminal peptide by PC2: a potential mechanism for its inactivation [9].
  • The amino acid sequence of preproSPC2 contains 689 aa and is 71% identical to human SPC2 [10].
  • SPC2 and SPC3 are two members of a family of subtilisin-related proteases which play essential roles in the processing of prohormones into their mature forms in the pancreatic B cell and many other neuroendocrine cells [10].
 

Chemical compound and disease context of PCSK2

 

Biological context of PCSK2

  • We have previously cloned and characterized the exon-intron organization of the human PC2 gene (gene symbol PCSK2), localized this gene to human chromosome 20 band p11.2 by fluorescence in situ hybridization, and identified a simple tandem-repeat DNA polymorphism (STRP) in intron 2 of the form (CA)n, suitable for genetic studies [1].
  • The hPC2 gene was localized to chromosome 20, band p11 [2].
  • In the present study, in vitro mutagenesis was used to identify the region within the 7B2 sequence responsible for the inhibition of PC2 [15].
  • Plasmids encoding proPC2 and various 7B2s were transiently transfected into human embryonic kidney (HEK293) cells and PC2 enzymatic activity and CT forms in each overnight conditioned medium were measured [16].
  • The screening of a larval cDNA library of the sheep blowfly Lucilia cuprina resulted in the isolation of two cDNAs encoding a PC2-like prohormone convertase [17].
 

Anatomical context of PCSK2

  • Finally, the in vivo regulation of pituitary PC2 mRNA by thyroid status was demonstrated in rats [4].
  • In contrast, PC2 transcripts were detected only in skin mast cells, whereas transcripts for paired basic amino acid converting enzyme 4 (PACE4) were present only in HMC-1 cells [18].
  • The mouse neuroblastoma cell line (Neuro 2 A) has been shown to contain the mRNA of a prohormone converting enzyme, PC2 [19].
  • Bile duct carcinoids also demonstrated higher expressions of PC1/3 than those of PC2 [20].
  • Our immunohistochemical studies disclosed the presence of PC1/3 and PC2 in non-neoplastic pituitary glands, especially in corticotrophs, gonadotrophs, and thyrotrophs [21].
 

Associations of PCSK2 with chemical compounds

  • Analysis of the level of chloramphenicol acetyltransferase activity with several deletion mutants identified the region from -1100 to -539 from the translation start site as essential for hPC2 promoter activity [2].
  • Interactions between the prohormone convertase 2 promoter and the thyroid hormone receptor [4].
  • To address the mechanism of T3 regulation of the PC2 gene, we used human PC2 (hPC2) promoter constructs transiently transfected into GH3 cells and found that triiodothyronine negatively and 9-cis-retinoic acid positively regulated hPC2 promoter activity [11].
  • Activation of both cAMP and PKC pathways increased PC1, but not PC2 or furin mRNA levels in SK-N-MCIXC cells [22].
  • PC2 processes proIAPP preferably at the NH2-terminal processing site, and PC1/3 processes proIAPP exclusively at the COOH-terminal site [23].
 

Physical interactions of PCSK2

  • In addition, we show that the transcription factor EGR-1 interacts with two distinct elements within the proximal human PC2 promoter region [24].
  • In vitro binding and Far Western blot experiments demonstrated that PC2 and FPC are in the same complex only if KIF3B is present, presumably by forming a PC2-KIF3B-FPC complex [25].
  • Site-directed mutagenesis of pro-PC2 further showed that a single residue replacement in the catalytic domain, Tyr-194 --> Asp, prevented pro-PC2 from binding 7B2 and blocked activation [26].
  • These results suggest that the interaction of Pa with its target sequence(s) prevent PC2 binding and thereby contribute towards increased IGFBP-1 gene transcription [27].
 

Enzymatic interactions of PCSK2

  • PC3 cleaves proinsulin first to generate a proinsulin conversion intermediate that is the preferred substrate of PC2 [28].
 

Regulatory relationships of PCSK2

  • Transfection experiments also demonstrate that EGR-1 is able to enhance PC2 promoter activity [24].
  • Previous studies have demonstrated that while the carboxyl-terminal portion of 7B2 (residues 155-186) regulates the enzymatic activity of PC2, the amino terminus of the molecule (residues 1-151) is required for maturation of proPC2 [29].
  • PC2 mRNA was down regulated by NaB while PC1 mRNA was unchanged [30].
  • Characterization of pro-opiomelanocortin processing in heterologous neuronal cells that express PC2 mRNA [31].
 

Other interactions of PCSK2

  • In contrast, in both cell types, human prorenin is not activated by either PC2 or furin [3].
  • Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p) [32].
  • PC3 was active initially at the N-terminal-IAPP junction and later at the C-terminus, whereas initial PC2 activity was at the IAPP-C-terminal junction [33].
  • We conclude that cleavage at the 7B2 furin consensus site is required to produce PC2 capable of efficient proteolytic inactivation of the CT peptide [16].
  • 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 [34]?
 

Analytical, diagnostic and therapeutic context of PCSK2

  • 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 [20].
  • A combination of site-directed mutagenesis and a cell-free translation/translocation system from Xenopus eggs was used to investigate the processing of the pro-PC2 precursor [35].
  • To further investigate the function(s) of SPC2 and SPC3 in amphioxus, we have determined the regional expression of these genes by using a reverse transcriptase-linked polymerase chain reaction (RT-PCR) assay [10].
  • Immunofluorescence experiments showed that PC2, FPC and KIF3B partially co-localized in primary cilia of over-confluent and perinuclear regions of sub-confluent cells [25].
  • The USA-derived coactivators PC2 and PC4 fully reconstitute the USA coactivator activity, both by repressing the basal level of transcription and by potentiating activator function to yield large increases in the levels of transcription induction [36].

References

  1. Association of the prohormone convertase 2 gene (PCSK2) on chromosome 20 with NIDDM in Japanese subjects. Yoshida, H., Ohagi, S., Sanke, T., Furuta, H., Furuta, M., Nanjo, K. Diabetes (1995) [Pubmed]
  2. Identification and analysis of the gene encoding human PC2, a prohormone convertase expressed in neuroendocrine tissues. Ohagi, S., LaMendola, J., LeBeau, M.M., Espinosa, R., Takeda, J., Smeekens, S.P., Chan, S.J., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  3. 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]
  4. Interactions between the prohormone convertase 2 promoter and the thyroid hormone receptor. Li, Q.L., Jansen, E., Brent, G.A., Naqvi, S., Wilber, J.F., Friedman, T.C. Endocrinology (2000) [Pubmed]
  5. 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]
  6. 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]
  7. Mechanism of the facilitation of PC2 maturation by 7B2: involvement in ProPC2 transport and activation but not folding. Muller, L., Zhu, X., Lindberg, I. J. Cell Biol. (1997) [Pubmed]
  8. Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion. Laurent, V., Kimble, A., Peng, B., Zhu, P., Pintar, J.E., Steiner, D.F., Lindberg, I. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  9. Internal cleavage of the inhibitory 7B2 carboxyl-terminal peptide by PC2: a potential mechanism for its inactivation. Zhu, X., Rouille, Y., Lamango, N.S., Steiner, D.F., Lindberg, I. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  10. Proprotein convertases in amphioxus: predicted structure and expression of proteases SPC2 and SPC3. Oliva, A.A., Steiner, D.F., Chan, S.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  11. Regulation of regional expression in rat brain PC2 by thyroid hormone/characterization of novel negative thyroid hormone response elements in the PC2 promoter. Shen, X., Li, Q.L., Brent, G.A., Friedman, T.C. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  12. Expression of prohormone convertase, PC2, in adrenocorticotropin-producing thymic carcinoid with elevated plasma corticotropin-releasing hormone. Kimura, N., Ishikawa, T., Sasaki, Y., Sasano, N., Onodera, K., Shimizu, Y., Kimura, I., Steiner, D.F., Nagura, H. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  13. The vasopressin precursor is not processed in the hypothalamus of Wolfram syndrome patients with diabetes insipidus: evidence for the involvement of PC2 and 7B2. Gabreëls, B.A., Swaab, D.F., de Kleijn, D.P., Dean, A., Seidah, N.G., Van de Loo, J.W., Van de Ven, W.J., Martens, G.J., Van Leeuwen, F.W. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  14. 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]
  15. 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]
  16. Inactivation of the 7B2 inhibitory CT peptide depends on a functional furin cleavage site. Hwang, J.R., Lindberg, I. J. Neurochem. (2001) [Pubmed]
  17. Isolation and characterization of insect PC2-like prohormone convertase cDNA. Mentrup, B., Londershausen, M., Spindler, K., Weidemann, W. Insect Mol. Biol. (1999) [Pubmed]
  18. 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]
  19. Post-translational processing of human procorticotrophin-releasing factor in transfected mouse neuroblastoma and Chinese hamster ovary cell lines. Brar, B., Sanderson, T., Wang, N., Lowry, P.J. J. Endocrinol. (1997) [Pubmed]
  20. 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]
  21. 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]
  22. 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]
  23. Aberrant processing of human proislet amyloid polypeptide results in increased amyloid formation. Paulsson, J.F., Westermark, G.T. Diabetes (2005) [Pubmed]
  24. Regulation of human prohormone convertase 2 promoter activity by the transcription factor EGR-1. Jansen, E., Ayoubi, T.A., Meulemans, S.M., Van De Ven, W.J. Biochem. J. (1997) [Pubmed]
  25. Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin. Wu, Y., Dai, X.Q., Li, Q., Chen, C.X., Mai, W., Hussain, Z., Long, W., Montalbetti, N., Li, G., Glynne, R., Wang, S., Cantiello, H.F., Wu, G., Chen, X.Z. Hum. Mol. Genet. (2006) [Pubmed]
  26. Structural elements of PC2 required for interaction with its helper protein 7B2. Zhu, X., Muller, L., Mains, R.E., Lindberg, I. J. Biol. Chem. (1998) [Pubmed]
  27. Interactions between liver nuclear proteins and the human insulin-like growth factor binding protein 1 promoter in the course of development. Babajko, S. Eur. J. Endocrinol. (1995) [Pubmed]
  28. 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]
  29. Involvement of a polyproline helix-like structure in the interaction of 7B2 with prohormone convertase 2. Zhu, X., Lamango, N.S., Lindberg, I. J. Biol. Chem. (1996) [Pubmed]
  30. Regulation of cell growth and expression of 7B2, PC2, and PC1/3 by TGFbeta 1 and sodium butyrate in a human pituitary cell line (HP75). Kobayashi, I., Jin, L., Ruebel, K.H., Bayliss, J.M., Hidehiro, O., Lloyd, R.V. Endocrine (2003) [Pubmed]
  31. Characterization of pro-opiomelanocortin processing in heterologous neuronal cells that express PC2 mRNA. Day, N.C., Lin, H., Ueda, Y., Meador-Woodruff, J.H., Akil, H. Neuropeptides (1993) [Pubmed]
  32. Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p). Maglott, D.R., Feldblyum, T.V., Durkin, A.S., Nierman, W.C. Mamm. Genome (1996) [Pubmed]
  33. Processing of synthetic pro-islet amyloid polypeptide (proIAPP) 'amylin' by recombinant prohormone convertase enzymes, PC2 and PC3, in vitro. Higham, C.E., Hull, R.L., Lawrie, L., Shennan, K.I., Morris, J.F., Birch, N.P., Docherty, K., Clark, A. Eur. J. Biochem. (2000) [Pubmed]
  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? Erkut, Z.A., Gabreëls, B.A., Eikelenboom, J., van Leeuwen, F.W., Swaab, D.F. Neuro Endocrinol. Lett. (2002) [Pubmed]
  35. Autocatalytic maturation of the prohormone convertase PC2. Matthews, G., Shennan, K.I., Seal, A.J., Taylor, N.A., Colman, A., Docherty, K. J. Biol. Chem. (1994) [Pubmed]
  36. Involvement of TFIID and USA components in transcriptional activation of the human immunodeficiency virus promoter by NF-kappaB and Sp1. Guermah, M., Malik, S., Roeder, R.G. Mol. Cell. Biol. (1998) [Pubmed]
 
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